Oxadiazolopyrazines and oxadiazolopyridines useful as mitochondrial uncouplers

ABSTRACT

The disclosure provide compounds of Formula I and the pharmaceutically acceptable salts thereof. The variables, R1, R2, R3, X1, X2, and Z are defined herein. Certain compounds of Formula I act as selective mitochondrial protonophore uncouplers that do not affect the plasma membrane potential. Compounds and salts of Formula I are useful for treating or decreasing the risk of conditions responsive to mitochondrial uncoupling, such as cancer, obesity, type II diabetes, fatty liver disease, insulin resistance, Parkinson&#39;s disease, ischemia reperfusion injury, heart failure, non-alcoholic fatty liver disease (NALFD), and non-alcoholic steatohepatitis (NASH). Because mitochondrial uncouplers decrease the production of reactive oxygen species (ROS), which are known to contribute to age-related cell damage, compounds of Formula I are useful for increasing lifespan. Compounds and salts of Formula I are also useful for regulating glucose homeostasis or insulin action in a patient.

CROSS REFERENCE TO RELATED APPLICATION

This application claims priority of U.S. Provisional Appl. No. 62/660,880, filed Apr. 20, 2018, which is hereby incorporated by reference in its entirety.

BACKGROUND

Cellular respiration is a physiological process with a fundamental goal of producing energy in the form of ATP. During cellular respiration, chemical energy derived from nutrients is converted into ATP. Specifically, the oxidation of nutrients in the mitochondrial matrix generates high-energy electron carriers nicotinamide adenine dinucleotide (NADH) and flavin adenine dinucleotide (FADH₂) that are oxidized by the mitochondrial electron transport chain (ETC) located in the mitochondrial inner-membrane (MIM). Electron flow through the ETC is an exergonic process that drives a series of proton pumps to efflux protons from the matrix into the inter-membrane space (IMS) against their concentration gradient. The resulting proton concentration (ΔpH) and electrical (ΔΨ) gradient is known as the proton-motive force (pmf). Protons that re-enter the mitochondrial matrix via ATP synthase drive endergonic production of ATP. Thus, mitochondrial ATP production involves the coupling of electron transport to phosphorylation reactions via a proton gradient across the MIM.

Mitochondrial uncoupling describes processes that uncouple nutrient oxidation from ATP production. Mitochondrial uncoupling is a normal physiological process that occurs as either basal or inducible proton leak from the intermembrane space. Basal proton leak accounts for ˜20-25% of the basal metabolic rate of mammals. The reason for such metabolic inefficiency is not entirely understood; however, membrane lipid composition and abundance of the adenine nucleotide translocase (ANT) are factors that contribute to basal rates of proton leak. Induced proton leak is driven by reactive species and fatty acids that activate uncoupling proteins (UCPs). UCPs are in the MIM and facilitate the transfer of protons into the matrix independent of ATP synthase.

There are five known UCPs in mammals, UCP1-5, that have distinct tissue localization. The best-characterized UCPs are UCP1 and UCP2. UCP1 is expressed in brown and beige adipose tissue and has a role in non-shivering thermogenesis. UCP1 is unlikely to operate as a simple proton channel, but instead transfers protons via a mechanism that requires long-chain fatty acids. In contrast, UCP2 has a broad tissue distribution and no role in thermogenesis. UCP2 uncouples mitochondria to prevent hyperpolarization and decrease mitochondrial superoxide production.

Small molecule mitochondrial uncouplers either act directly as protonophores by transporting protons into the matrix independently of protein complexes or, alternatively, mediate uncoupling via proteins such as ANT. Protonophoric uncouplers are lipophilic enough to enable passage through the MIM and weakly acidic to enable partial and reversible pH-dependent ionization. Mitochondrial uncoupling has two major phenotypes of therapeutic relevance including increased nutrient oxidation to compensate for lack of efficiency in ATP production and decreasing superoxide production from the ETC. The ETC is a primary source of reactive oxygen species (ROS) in most tissues. ETC-derived superoxide formation occurs via a non-enzymatic process when single electrons on co-enzymes or prosthetic groups in redox centers interact with molecular oxygen. Single electrons in the ETC only transiently exist in redox centers and the dwell time for single electrons in an unstable state increases the likelihood of superoxide production. Mitochondrial uncouplers decrease mitochondrial superoxide production by stimulating faster electron transfer that decreases the dwell time for single electrons in the ETC.

The therapeutic potential of mitochondrial uncouplers is related to their dual roles in increasing nutrient oxidation and decreasing ROS production from the ETC. On the one hand, increased nutrient oxidation promotes leanness and is a therapeutic strategy to treat obesity and related metabolic diseases. On the other hand, mitochondrial ROS are linked to numerous pathologies including ischemia-reperfusion injury, inflammation, insulin resistance, neurodegeneration, and many other pathologies. Importantly, mitochondrial uncouplers prevent ROS production, which is advantageous compared to antioxidants that scavenge ROS that has already been produced. As such, decreasing mitochondrial ROS production has significant therapeutic potential with advantages over antioxidant scavengers.

Mitochondria regulate cellular metabolism and play an important role in the pathogenesis of some of the most prevalent human diseases including obesity, cancer, diabetes, neurodegeneration, and heart disease. Many of these diseases can be improved using pharmacological agents like mitochondrial uncouplers that lessen mitochondrial oxidative damage and increase energy expenditure. Genetic and pharmacologic uncoupling have beneficial effects on disorders that are linked to mitochondrial oxidative stress, such as ischemic-reperfusion injury, Parkinson's disease, insulin resistance, aging, and heart failure, and disorders that stand to benefit from increased energy expenditure such as obesity.

Mitochondrial uncouplers are known and have been shown to be effective for treating obesity. For example, 2,4-dinitrophenol (DNP) is a well-known small molecule mitochondrial protonophore that results in weight loss in humans. Patients consuming ˜300 mg/d steadily shed an average of 1.5 pounds per week over the course of several months without changes in food intake. Similarly, mice treated with DNP demonstrate improved serological glucose, triglyceride, and insulin levels, as well as decreased oxidative damage, reduced body weight, and increased longevity. However, DNP has off-target effects on other cellular membranes resulting in a narrow therapeutic index. DNP was subsequently withdrawn from the North American market by the US Food and Drug Administration in 1938. Currently, there are no uncoupler drugs that are safe enough for use in humans.

The development of a selective mitochondrial protonophore uncoupler that does not affect the plasma membrane potential would broaden the safety margin of mitochondrial uncouplers and provide renewed hope that mitochondrial uncoupling can be targeted for the treatment of obesity, type II diabetes, and other diseases, disorders, and conditions related to mitochondrial function. There is a long felt need in the art for compositions and methods useful for preventing and treating obesity, diabetes, regulating glucose homeostasis, reducing adiposity, protecting from ischemic-reperfusion injury, and regulating insulin action using mitochondrial uncouplers as well as for compounds useful as mitochondrial uncouplers. The present disclosure satisfies these needs.

SUMMARY

This disclosure provides compounds of Formula A

and the pharmaceutically acceptable salts thereof.

With Formula A, the variables, X¹, X², Y¹, Y², Y³, Z, R¹, R², and R³ carry the following definitions.

Z is O or S.

X¹ and X² are CH or N, with at least one of X¹ and X² being N.

Y¹, Y², and Y³ are selected from N, O, and CH, wherein at least one of Y¹, Y², and Y³ is N, and at least one of Y¹, Y², and Y³ is an oxygen. The 5 membered-ring containing Y¹, Y², and Y³ is aromatic.

R¹ is hydrogen or C₁-C₈alkyl, C₂-C₈alkenyl, or C₂-C₈alkynyl.

R² is C₁-C₈alkyl, C₂-C₈alkenyl, or C₂-C₈alkynyl; or R² is —C₀-C₄alkyl(C₃-C₇cycloalkyl), —C₀-C₄alkyl(bridged C₇-C₁₂cycloalkyl), —C₀-C₄alkyl(aryl), —C₀-C₄alkyl(mono- or bi-cyclic heteroaryl), or —C₀-C₄alkyl(4- to 7-membered heterocycloalkyl), each of which is optionally substituted with one or more substituents independently chosen from R¹¹ and 0 or 1 substituents R¹²; or

R¹ and R² are joined to form a 3-7 membered cyclic ring in which one carbon is optionally replaced by N, S, or O.

R³ is H or C₁-C₈alkyl, C₂-C₈alkenyl, or C₂-C₈alkynyl, or

R³ is —C₀-C₄alkyl(C₃-C₇cycloalkyl) or —C₀-C₄alkyl(aryl), which is optionally substituted with one or more independently chosen R¹¹ substituents.

In each C₀-C₄alkyl, C₁-C₈alkyl, C₂-C₈alkenyl, or C₂-C₈alkynyl in the definitions of R¹, R², and R³ one or more carbon atoms is optionally replaced by O, NR¹⁰, —C(O)—, —C(O)O—, —OC(O), —S(O)n—, —C(O)NR¹⁰—, or —NR¹⁰C(O)— where n is 0, 1, or 2, and in which the C₀-C₄alkyl, C₁-C₈ alkyl, C₂-C₈alkenyl, or C₂-C₈alkynyl is optionally substituted with one or more substituents R¹³.

R¹⁰ is independently chosen at each occurrence from hydrogen, C₁-C₆alkyl, and —C₀-C₂alkyl(C₃-C₇cycloalkyl).

R¹¹ is independently selected at each occurrence from halogen, hydroxyl, amino, nitro, cyano, —CHO, —COOH, oxo, halosulfanyl, and C₁-C₈alkyl, C₂-C₈alkenyl, and C₂-C₈alkynyl, wherein in each C₁-C₈alkyl, C₂-C₈alkenyl, and C₂-C₈alkynyl, in the definition of R¹¹ one or more carbon atoms is optionally replaced by O, NR¹⁰, —C(O)—, —C(O)O—, —OC(O), —S(O)n—, —S(O)nNR¹⁰,

—NR¹⁰S(O)n-, —NR¹⁰C(O)NR¹⁰, —C(O)NR¹⁰—, or —NR¹⁰C(O)— where n is 0, 1, or 2, and in which each C₀-C₄alkyl, C₁-C₈alkyl, C₂-C₈alkenyl, or C₂-C₈alkynyl is optionally substituted with one or more substituents R¹³.

R¹² is selected from —C₀-C₄alkyl(C₃-C₇cycloalkyl), —O—C₀-C₄alkyl(C₃-C₇cycloalkyl), —C₀-C₄alkyl(aryl), —O—C₀-C₄alkyl(aryl), —C₀-C₄alkyl(5- to 6-membered heteroaryl), —O—C₀-C₄alkyl(5- to 6-membered heteroaryl), —C₀-C₄alkyl(3- to 6-membered heterocycloalkyl), and —O—C₀-C₄alkyl(3- to 6-membered heterocycloalkyl), each of which is optionally substituted with one or more substituents independently chosen from halogen, hydroxyl, amino, nitro, cyano, —CHO, —COOH, oxo, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₆alkyl, C₁-C₆alkoxy, C₁-C₆alkylester, —C₀-C₄alkyl(mono- or di-C₁-C₆alkylamino), C₂-C₆alkanoyl, C₂-C₆alkenyl, and C₂-C₆alkynyl.

R¹³ is independently chosen at each occurrence from halogen, hydroxyl, amino, nitro, cyano, —CHO, —COOH, oxo, C₃-C₇cycloalkyl, and phenyl.

The disclosure includes a pharmaceutical composition, comprising a compound or salt of Formula A, together with a pharmaceutically acceptable excipient.

The disclosure includes a method of treating or preventing a condition responsive to mitochondrial uncoupling, comprising administering a therapeutically effective amount of a compound or salt of Formula A to a patient in need of such treatment. Conditions responsive to mitochondrial uncoupling include obesity, type II diabetes, fatty liver disease, insulin resistance, Parkinson's disease, ischemia reperfusion injury, heart failure, non-alcoholic fatty liver disease (NALFD), and non-alcoholic steatohepatitis (NASH).

The disclosure also includes a method of increasing lifespan comprising administering an effective amount of a compound of Formula I, or salt thereof, to a human or non-human animal Increasing lifespan can be via delaying aging by delaying the onset of age-related disease, or age related changes, including neurodegenerative diseases, an age related cognitive decline, or an age-related decrease in motorneuron responses. The disclosure includes a method of increasing lifespan by delaying the onset of diseases associated with aging, comprising administering an effective amount of a compound of Formula I, or salt thereof, to a human or non-human animal.

The disclosure includes a method of regulating glucose homeostasis or insulin action in a patient comprising administering a therapeutically effective amount of a compound or salt of Formula A to a patient in need thereof.

The disclosure also includes a method of treating hyperlipidemia, glycemia, glucose tolerance, insulin sensitivity, adiposity, insulin resistance, obesity, or diabetes in a patient comprising administering a therapeutically effective amount of a compound of any one of claims 1 to 30 to the patient.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1A-1K. Oxygen consumption rate as a percent of basal oxygen consumption as a function of compound concentration. The assay is performed using the protocol given in Example 252. FIG. 1A, compound 1-3; FIG. 1B, compound 1-4; FIG. 1C, compound 1-7; FIG. 1D, compound 1-8; FIG. 1E, compound 1-9; FIG. 1F, compound 1-10; FIG. 1G, compound 1-11; FIG. 1H, compound 1-20; FIG. 1I, compound 1-44; FIG. 1J, compound 1-45; FIG. 1-K, compound 46.

FIGS. 2A-2C. Diet induced obesity reversal data, for mice given a regular chow diet, a Western diet, or a Western diet plus compound 1-112. FIG. 1A, Body mass versus time; FIG. 1B, fat mass (measured by EchoMRI) versus time; FIG. 1C, food intake (last 14 days) versus time.

DETAILED DESCRIPTION

In the description and claims, terms will carry the definitions set forth in this section unless the stated otherwise or contrary to the context. Unless defined otherwise, all technical and scientific terms used herein have the commonly understood by one of ordinary skill in the art to which the disclosure pertains. Although any methods and materials similar or equivalent to those described herein may be useful in the practice or testing of the embodiments of this disclosure; preferred methods and materials are described below.

The terms “a” and “an” do not denote a limitation of quantity, but rather denote the presence of at least one of the referenced item. The term “or” means “and/or”. The term “about,” as used herein, means approximately, in the region of, roughly, or around. When the term “about” is used in conjunction with a numerical range, it modifies that range by extending the boundaries above and below the numerical values set forth. In general, the term “about” is used herein to modify a numerical value above and below the stated value by a variance of 10%. Therefore, about 50% means in the range of 45% 55%.

Numerical ranges recited herein by endpoints include all numbers and fractions subsumed within that range (e.g. 1 to 5 includes 1, 1.5, 2, 2.75, 3, 3.90, 4, and 5).

The terms “additional therapeutically active compound” or “additional therapeutic agent,” refers to the use or administration of a compound for an additional therapeutic use for a particular injury, disease, or disorder being treated. Such a compound, for example, could include one being used to treat an unrelated disease or disorder, or a disease or disorder which may not be responsive to the primary treatment for the injury, disease or disorder being treated.

As used herein, the terms “administration of” and or “administering” a compound should be understood to mean providing a compound of the disclosure to a subject in need of treatment.

An “agonist” is a composition of matter which, when administered to a mammal such as a human, enhances or extends a biological activity attributable to the level or presence of a target compound or molecule of interest in the subject.

“Alleviating a disease or disorder symptom,” means reducing the severity of the symptom or the frequency with which such a symptom is experienced by a subject, or both.

An “antagonist” is a composition of matter which when administered to a mammal such as a human, inhibits a biological activity attributable to the level or presence of a compound or molecule of interest in the subject.

A “Compound of Formula A” as used herein, refers to any compound within the scope of Formula A and, unless the context indicates otherwise, includes the pharmaceutically acceptable salts of Formula A. A Compound of Formula A encompasses A Compound of Formula I and its pharmaceutically acceptable salts.

The terms “comprises,” “comprising,” and the alternate transitional phrases “includes,” “including,” “contain,” and “containing” are open ended transitional phrases having the meaning ascribed to them in U.S. Patent Law. “Comprises” and the other open-ended terms encompass the intermediate term “consisting essentially of” and the closed ended terms “consisting of” and “consists of.” Claims reciting one of the open-ended transitional phrases can be written with any other transitional phrase, which may be more limiting, unless clearly precluded by the context or art.

The term “delivery vehicle” refers to any kind of device or material which can be used to deliver compounds in vivo or can be added to a composition comprising compounds administered to a plant or animal. This includes, but is not limited to, implantable devices, aggregates of cells, matrix materials, gels, etc.

A “disease” is a state of health of an animal wherein the animal cannot maintain homeostasis, and wherein if the disease is not ameliorated then the animal's health continues to deteriorate. In contrast, a “disorder” in an animal is a state of health in which the animal is able to maintain homeostasis, but in which the animal's state of health is less favorable than it would be in the absence of the disorder. Left untreated, a disorder does not necessarily cause a further decrease in the animal's state of health.

As used herein, an “effective amount” or “therapeutically effective amount” means an amount sufficient to produce a selected effect, such as alleviating symptoms of a disease or disorder. In the context of administering compounds in the form of a combination, such as multiple compounds, the amount of each compound, when administered in combination with another compound(s), may be different from when that compound is administered alone. Thus, an effective amount of a combination of compounds refers collectively to the combination as a whole, although the actual amounts of each compound may vary.

As used in the specification and the appended claims, the terms “for example,” “for instance,” “such as,” “including” and the like are meant to introduce examples that further clarify more general subject matter. Unless otherwise specified, these examples are provided only as an aid for understanding the disclosure and are not meant to be limiting in any fashion.

The terms “formula” and “structure” are used interchangeably herein.

The term “inhibit,” as used herein, refers to the ability of a compound of the disclosure to reduce or impede a described function, such as having inhibitory sodium channel activity. Preferably, inhibition is by at least 10%, more preferably by at least 25%, even more preferably by at least 50%, and most preferably, the function is inhibited by at least 75%. The terms “inhibit”, “reduce”, and “block” are used interchangeably herein.

As used herein “injecting or applying” includes administration of a compound of the disclosure by any number of routes and means including, but not limited to, topical, oral, buccal, intravenous, intramuscular, intra-arterial, intramedullary, intrathecal, intraventricular, transdermal, subcutaneous, intraperitoneal, intranasal, enteral, topical, sublingual, vaginal, ophthalmic, pulmonary, or rectal means.

As used herein, an “instructional material” includes a publication, a recording, a diagram, or any other medium of expression which can be used to communicate the usefulness of compound of the disclosure in the kit for effecting alleviation of the various diseases or disorders recited herein. Optionally, or alternately, the instructional material may describe one or more methods of alleviating the diseases or disorders in a cell or a tissue of a mammal. The instructional material of the kit of the disclosure may, for example, be affixed to a container which contains the identified disclosure compound or be shipped together with a container which contains the identified compound.

Alternatively, the instructional material may be shipped separately from the container with the intention that the instructional material and the compound be used cooperatively by the recipient.

The term, “mitochondrial uncoupling,” also referred to as “uncoupling,” refers to the process whereby protons enter the mitochondrial matrix via a pathway independent of ATP synthase and thereby uncouple nutrient oxidation from ATP production. This process can be pharmacologically induced by small molecule mitochondrial protonophores, which directly shuttle protons across the mitochondrial inner membrane into the matrix. The primary pathway for energy production in aerobic cells involves the oxidation of nutrients (including fats, carbohydrates, and amino acids) in mitochondria, which promotes the efflux of protons out of the mitochondrial matrix. This process creates a pH and electrochemical gradient across the mitochondrial inner membrane. Protons normally re-enter the mitochondrial matrix via ATP synthase, which results in ATP production. Protons can also re-enter the mitochondrial matrix via pathways independent of ATP synthase, which uncouples' nutrient oxidation and proton efflux from ATP production.

The term “modulate,” means changing the level of an activity, function, or process. The term “modulate” encompasses both inhibiting and stimulating an activity, function, or process.

As used herein, “parenteral administration” of a pharmaceutical composition includes any route of administration characterized by physical breaching of a tissue of a subject and administration of the pharmaceutical composition through the breach in the tissue. Parenteral administration thus includes, but is not limited to, administration of a pharmaceutical composition by injection of the composition, by application of the composition through a surgical incision, by application of the composition through a tissue-penetrating non-surgical wound, and the like. In particular, parenteral administration is contemplated to include, but is not limited to, subcutaneous, intraperitoneal, intramuscular, intrasternal injection, and kidney dialytic infusion techniques.

The term “per application” as used herein refers to administration of a compositions, drug, or compound to a subject.

The term “pharmaceutical composition” shall mean a composition comprising at least one active ingredient and a pharmaceutically acceptable carrier, such as a pharmaceutically acceptable excipient.

A “pharmaceutically acceptable excipient” means an excipient that is useful in preparing a pharmaceutical composition/combination that is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes an excipient that is acceptable for veterinary use as well as human pharmaceutical use. The term also encompasses any of the inactive agents approved for use pharmaceutical compositions in by a regulatory agency of the US Federal government or listed in the US Pharmacopeia for use in animals, including humans.

The term “pharmaceutically acceptable carrier” includes any of the standard pharmaceutical carriers, such as a phosphate buffered saline solution, water, emulsions such as an oil/water or water/oil emulsion, and various types of wetting agents. The term also encompasses any of the agents approved by a regulatory agency of the US Federal government or listed in the US Pharmacopeia for use in animals, including humans.

“Pharmaceutically acceptable” means physiologically tolerable, for either human or veterinary application. As used herein, “pharmaceutical compositions” include formulations for human and veterinary use.

“Plurality” means at least two.

The term “prevent,” as used herein, means to stop something from happening or to significantly reduce the likelihood of something happening, such as by taking advance measures against something possible or probable outcome. In the context of medicine, “prevention” includes an action taken to decrease the chance of getting a disease or condition.

A “preventive” or “prophylactic” treatment is a treatment administered to a subject who does not exhibit signs, or exhibits only early signs, of a disease or disorder. A prophylactic or preventative treatment is administered for the purpose of decreasing the risk of developing pathology associated with developing the disease or disorder.

A “prodrug” refers to an agent that is converted into the parent drug in vivo. Prodrugs are often useful because, in some situations, they may be easier to administer than the parent drug. They may, for instance, be bioavailable by oral administration whereas the parent is not. The prodrug may also have improved solubility in pharmaceutical compositions over the parent drug, or may demonstrate increased palatability or be easier to formulate.

A “subject” of analysis, diagnosis, or treatment is an animal. Such animals include mammals, preferably a human. As used herein, a “subject in need thereof” is a patient, animal, mammal, or human, who will benefit from the method of this disclosure.

The term “symptom,” as used herein, refers to any morbid phenomenon or departure from the normal in structure, function, or sensation, experienced by the patient and indicative of disease. In contrast, a “sign” is objective evidence of disease. For example, a bloody nose is a sign. It is evident to the patient, doctor, nurse and other observers.

A “therapeutic” treatment is a treatment administered to a subject who exhibits signs of pathology for the purpose of diminishing or eliminating those signs.

A “therapeutically effective amount” of a compound is that amount of compound which is sufficient to provide a beneficial effect to the subject to which the compound is administered.

As used herein, “treat,” “treating”, or “treatment” includes treating, ameliorating, or inhibiting an injury or disease related condition or a symptom of an injury or disease related condition. In one embodiment the disease, injury or disease related condition or a symptom of an injury or disease related condition is prevented; while another embodiment provides prophylactic treatment of the injury or disease related condition or a symptom of an injury or disease related condition.

Chemical Definitions

“Alkyl” is a branched or straight chain saturated aliphatic hydrocarbon group, having the specified number of carbon atoms, generally from 1 to about 8 carbon atoms. The term C₁-C₆-alkyl as used herein indicates an alkyl group having from 1, 2, 3, 4, 5, or 6 carbon atoms. Other embodiments include alkyl groups having from 1 to 6 carbon atoms, 1 to 4 carbon atoms or 1 or 2 carbon atoms, e.g. C₁-C₈-alkyl, C₁-C₄-alkyl, and C₁-C₂-alkyl. Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, 3-methylbutyl, t-butyl, n-pentyl, sec-pentyl, heptyl, and octyl. “C₀-C_(n) alkyl” is used together with another group, e.g. C₀-C₄alkyl(C₃-C₇cycloalkyl), to indicate the other group, in this case C₃-C₇cycloalkyl, is bound to the group it substitutes either by a single covalent bond (C₀) or attached through an alkylene linker having the indicated number of carbon atoms.

“Alkenyl” is a branched or straight chain aliphatic hydrocarbon group having one or more double carbon-carbon bonds that may occur at any stable point along the chain, having the specified number of carbon atoms. Examples of alkenyl include, but are not limited to, ethenyl, propenyl, 1, 3-butadienyl, 1-butenyl, hexenyl, and pentenyl.

“Alkynyl” is a branched or straight chain aliphatic hydrocarbon group having one or more triple carbon-carbon bonds that may occur at any stable point along the chain, having the specified number of carbon atoms. Examples of alkynyl include, but are not limited to, ethynyl, propynyl, 1-butynyl, 2-butynyl, and 1-pentynyl.

“Alkanoyl” is an alkyl group as defined above covalently bound to the group it substitutes by an carbonyl bridge (—C(═O)—). The carbonyl oxygen is included in the count of carbons in the substituted group. A C₂alkanoyl is —C(═O)CH₃.

“Alkoxy” is an alkyl group as defined above with the indicated number of carbon atoms covalently bound to the group it substitutes by an oxygen bridge (—O—). Examples of alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, 2-butoxy, t-butoxy, n-pentoxy, 2-pentoxy, 3-pentoxy, isopentoxy, neopentoxy, n-hexoxy, 2-hexoxy, 3-hexoxy, and 3-methylpentoxy.

“Alkylamino” is an alkyl group as defined herein covalently bound to the group it substitutes by an amino linkage. An alkylamino group can be a mono-alkyl group in which the amino is a secondary amino (alkylNH—) or a di-alkyl group in which the amino is a tertiary amino, (alkyl1)(alkyl2)N—. The alkyl groups of a di-alkylamino are the same or different.

“Alkylester” is an alkyl group as defined herein covalently bound to the group it substitutes by an ester linkage. The ester linkage may be in either orientation, e.g., a group of the formula —OC(O)-alkyl or a group of the formula —C(O)O-alkyl.

“Aryl” indicates a mono-, bi- or tri-cyclic ring system having at least one aromatic ring. Aryl groups contain only carbon in the aromatic ring or rings. An aryl group may be fused to a non aromatic ring containing N, O, or S heteroatoms. Typical aryl groups contain 1 to 3 separate, fused, or pendant rings and from 6 to about 18 ring atoms, without heteroatoms as ring members. When indicated, such aryl groups may be further substituted with carbon or non-carbon atoms or groups. Example include phenyl, naphthyl, bi-phenyl, tetrahydronaphthyl, indanyl, and indenyl group.

“Cycloalkyl” is a saturated hydrocarbon ring group, having the specified number of carbon atoms. Monocyclic cycloalkyl groups typically have from 3 to about 8 carbon ring atoms, from 3 to 7 ring atoms, or from 3 to 6 (3, 4, 5, or 6) carbon ring atoms. Cycloalkyl substituents may be pendant from a substituted nitrogen, oxygen, or carbon atom, or a substituted carbon atom that may have two substituents may have a cycloalkyl group, which is attached as a spiro group. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

A “bridged cycloalkyl” is a cycloalkyl group that has two or more rings containing only carbon ring atoms, and one of the carbon rings contains a “bridge” of 1 carbon atom or 2-3 unbranched carbon atoms connected to two “bridgehead” atoms in the carbon ring. The bridgehead atoms are usually non-adjacent carbon ring atoms. Examples of bridge cycloalkyl groups include, but are not limited to, bicyclo[2.2.2]octanyl, bicyclo[3.3.1]nonanyl, adamantanyl, and bicyclo[3.3.3]undecanyl groups.

“Halogen” or “halo” includes bromo, chloro, fluoro, and iodo.

“Haloalkyl” indicates both branched and straight-chain alkyl groups having the specified number of carbon atoms, substituted with 1 or more halogen atoms, up to the maximum allowable number of halogen atoms. Examples of haloalkyl include, but are not limited to, trifluoromethyl, difluoromethyl, 2-fluoroethyl, 2,2,2-trifluoroethyl, and penta-fluoroethyl.

“Haloalkoxy” indicates a haloalkyl group as defined herein attached through an oxygen bridge (oxygen of an alcohol radical).

“Halosulfanyl” is a sulfur substituted with one or more halogen atoms, up to the maximum allowable number of halogen atoms.

“Heteroaryl” is a ring or ring system having at least one aromatic ring containing a heteroatom independently chosen from N, O, and S with remaining ring atoms being carbon. Fused rings may or may not contain heteroatoms and need not be aromatic. It is preferred that the total number of heteroatoms in a heteroaryl ring system is not more than 4 and that the total number of S and O atoms in a heteroaryl ring system is not more than 2. Monocyclic heteroaryl groups typically have from 5 to 7 ring atoms. In some embodiments bicyclic heteroaryl groups are 9- to 10-membered heteroaryl groups, that is, groups containing 9 or 10 ring atoms in which one 5- to 7-member aromatic ring is fused to a second aromatic or non-aromatic ring. When the total number of S and O atoms in an aromatic ring of the heteroaryl group exceeds 1, these heteroatoms are not adjacent to one another. Examples of heteroaryl groups include, but are not limited to, oxazolyl, pyranyl, pyrazinyl, pyrazolopyrimidinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, quinolinyl, tetrazolyl, thiazolyl, thienylpyrazolyl, thiophenyl, triazolyl, benzo[d]oxazolyl, benzofuranyl, benzothiazolyl, benzothiophenyl, benzoxadiazolyl, dihydrobenzodioxynyl, furanyl, imidazolyl, indolyl, and isoxazolyl.

“Heterocycloalkyl” is a saturated cyclic group containing 1 or more ring atoms independently chosen from N, O, and S with remaining ring atoms being carbon. Examples of heterocycloalkyls include tetrahydropyranyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, oxazolidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, thiazolidinyl, and pyrrolidinyl.

“Pharmaceutically acceptable salts” includes derivatives of the disclosed compounds in which the parent compound is modified by making inorganic and organic, non-toxic, acid or base addition salts thereof. The salts of the present compounds can be synthesized from a parent compound that contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting free acid forms of these compounds with a stoichiometric amount of the appropriate base (such as Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate, or the like), or by reacting free base forms of these compounds with a stoichiometric amount of the appropriate acid Alkali metal (for example, sodium, potassium or lithium) or alkaline earth metal (for example calcium) salts of organic (e.g., carboxylic) acids can also be made.

Such reactions are typically carried out in water or in an organic solvent, or in a mixture of the two.

Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines or nitrogen-containing heteroaryl rings (e.g. pyridine, quinoline, isoquinoline); alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts include the conventional non-toxic salts and the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, conventional non-toxic acid salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, malonic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, mesylic, besylic, besylic, sulfanilic, 2-acetoxybenzoic, fumaric, succinic, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, α-ketoglutarate, α-glycerophosphate, isethionic, HO₂C—(CH₂)_(n) CO₂H where n is 0-4, and the like.

Salts derived from inorganic bases, include by way of example only, sodium, potassium, lithium, ammonium, calcium and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary and tertiary amines, such as alkyl amines, dialkyl amines, trialkyl amines, substituted alkyl amines, di(substituted alkyl) amines, tri(substituted alkyl) amines, alkenyl amines, dialkenyl amines, trialkenyl amines, substituted alkenyl amines, di(substituted alkenyl) amines, tri(substituted alkenyl) amines, cycloalkyl amines, di(cycloalkyl) amines, tri(cycloalkyl) amines, substituted cycloalkyl amines, disubstituted cycloalkyl amine, trisubstituted cycloalkyl amines, cycloalkenyl amines, di(cycloalkenyl) amines, tri(cycloalkenyl) amines, substituted cycloalkenyl amines, disubstituted cycloalkenyl amine, trisubstituted cycloalkenyl amines, aryl amines, diaryl amines, triaryl amines, heteroaryl amines, diheteroaryl amines, triheteroaryl amines, heterocyclic amines, diheterocyclic amines, triheterocyclic amines, mixed di- and tri-amines where at least two of the substituents on the amine are different and are selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, heteroaryl, heterocyclic, and the like. Also included are amines where the two or three substituents, together with the amino nitrogen, form a heterocyclic or heteroaryl group. Examples of suitable amines include, by way of example only, isopropylamine, trimethyl amine, diethyl amine, tri(iso-propyl) amine, tri(n-propyl) amine, ethanolamine, 2-dimethylaminoethanol, tromethamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, Nalkylglucamines, theobromine, purines, piperazine, piperidine, morpholine, Nethylpiperidine, and the like. It should also be understood that other carboxylic acid derivatives would be useful in the practice of this disclosure, for example, carboxylic acid amides, including carboxamides, lower alkyl carboxamides, dialkyl carboxamides, and the like.

Lists of additional suitable salts may be found, e.g., in G. Steffen Paulekuhn, et al., Journal of Medicinal Chemistry 2007, 50, 6665 and Handbook of Pharmaceutical Salts: Properties, Selection and Use, P. Heinrich Stahl and Camille G. Wermuth Editors, Wiley-VCH, 2002.

The term “substituted” means that any one or more hydrogens on the designated atom or group is replaced with a selection from the indicated group, provided that the designated atom's normal valence is not exceeded. Unless otherwise specified, each substituent is selected independently of other substituents. “Optionally substituted” means that 0 to the maximum allowable number of substituents are present. When the substituent is oxo (i.e., ═O) then 2 hydrogens on the atom are replaced. When an oxo group substitutes a heteroaromatic moiety, the resulting molecule can sometimes adopt tautomeric forms. For example, a pyridyl group substituted by oxo at the 2- or 4-position can sometimes be written as a pyridine or hydroxypyridine. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds or useful synthetic intermediates. A stable compound or stable structure is meant to imply a compound that is sufficiently robust to survive isolation from a reaction mixture and subsequent formulation into an effective therapeutic agent. Unless otherwise specified, substituents are named into the core structure. For example, it is to be understood that aminoalkyl means the point of attachment of this substituent to the core structure is in the alkyl portion and alkylamino means the point of attachment is a bond to the nitrogen of the amino group. However, a dash (“-”) indicates a point of attachment for a substituent. —C₁-C₄alkyl(cycloalkyl) is attached at the 1 to 4 carbon alkylene linker.

Certain compounds of the disclosure may contain one or more asymmetric elements such as stereogenic centers, stereogenic axes and the like, e.g. asymmetric carbon atoms, so that the compounds can exist in different stereoisomeric forms. These compounds can be, for example, racemates or optically active forms. For compounds with two or more asymmetric elements, these compounds can additionally be mixtures of diastereomers. For compounds having asymmetric centers, it should be understood that all of the optical isomers and mixtures thereof are encompassed. In these situations, single enantiomers, i.e., optically active forms, can be obtained by asymmetric synthesis, synthesis from optically pure precursors, or by resolution of the racemates. Resolution of the racemates can also be accomplished, for example, by conventional methods such as crystallization in the presence of a resolving agent, or chromatography, using, for example using a chiral HPLC column. In addition, compounds with carbon-carbon double bonds may occur in Z- and E-forms, with all isomeric forms of the compounds being included in the present disclosure.

The disclosure includes deuterated compounds of Formula A and Formula I in which any hydrogen is replaced by a deuterium. “Deuterated” mean that a hydrogen at the specified position is replaced by deuterium. In any sample of a compound of Formula A and Formula I in which a position is deuterated some discrete molecules of the compound of Formula A and Formula I will likely have hydrogen, rather than deuterium, at the specified position. However the percent of molecules of the compound of Formula I-A or I-B in the sample which have deuterium at the specified position will be much greater than would naturally occur. The deuterium at the deuterated position is enriched. The term “enriched” as used herein, refers to the percentage of deuterium versus other hydrogen species at that location. As an example, if it is said that a position in the compound of Formula I contains 50% deuterium enrichment, that means that rather than hydrogen at the specified position the deuterium content is 50%. For clarity, it is confirmed that the term “enriched” as used herein does not mean percentage enriched over natural abundance. In one embodiment, deuterated compounds of Formula A and Formula I will have at least 10% deuterium enrichment at any deuterated position. In other embodiments, there will be at least 50%, at least 90%, or at least 95% deuterium enrichment at the specified deuterated position or positions. A “deuterated substituent” is a substituent in which at least one hydrogen is replaced by deuterium at the specified percent enrichment. “Optionally deuterated” means that the position may be at either hydrogen and the amount of deuterium at the position is only the naturally occurring level of deuterium or the position is enriched with deuterium above the naturally occurring deuterium level.

Where a compound exists in various tautomeric forms, the disclosure is not limited to any one of the specific tautomers, but rather includes all tautomeric forms. The compounds of the disclosure may exist in tautomeric forms. both mixtures and separate individual tautomers are included. For example

also includes

Chemical Description

This disclosure provides a compound of Formula I

or a pharmaceutically acceptable salts thereof. The variables of Formula I, e.g. X¹, X², R¹, R², R³, and Z carry the following definitions.

X¹ and X² are C or N, with at least one of X¹ and X² being N.

Z is O, NH, or S.

R¹ is hydrogen or C₁-C₈alkyl, C₂-C₈alkenyl, or C₂-C₈alkynyl.

R² is C₁-C₈alkyl, C₂-C₈alkenyl, or C₂-C₈alkynyl; or

R² is —C₀-C₄alkyl(C₃-C₇cycloalkyl), —C₀-C₄alkyl(bridged C₇-C₁₂cycloalkyl), —C₀-C₄alkyl(aryl), —C₀-C₄alkyl(mono- or bi-cyclic heteroaryl), or —C₀-C₄alkyl(4- to 7-membered heterocycloalkyl), each of which is optionally substituted with one or more substituents independently chosen from R¹¹ and 0 or 1 substituents R¹²; or

R¹ and R² are joined to form a 3-7 membered cyclic ring in which one carbon is optionally replaced by N, S, or O.

R³ is H or C₁-C₈alkyl, C₂-C₈alkenyl, or C₂-C₈alkynyl, or

R³ is —C₀-C₄alkyl(C₃-C₇cycloalkyl) or —C₀-C₄alkyl(aryl), which is optionally substituted with one or more independently chosen R¹¹ substituents.

In each C₀-C₄alkyl, C₁-C₈alkyl, C₂-C₈alkenyl, or C₂-C₈alkynyl in the definitions of R¹, R², and R³ one or more carbon atoms is optionally replaced by O, NR¹⁰, —C(O)—, —C(O)O—, —OC(O), —S(O)n-, —C(O)NR¹⁰—, or —NR¹⁰C(O)— where n is 0, 1, or 2, and in which the C₀-C₄alkyl, C₁-C₈ alkyl, C₂-C₈alkenyl, or C₂-C₈alkynyl is optionally substituted with one or more substituents R¹³.

R¹⁰ is independently chosen at each occurrence from hydrogen, C₁-C₆alkyl, and —C₀-C₂alkyl(C₃-C₇cycloalkyl).

R¹¹ is independently selected at each occurrence from halogen, hydroxyl, amino, nitro, cyano, —CHO, —COOH, oxo, halosulfanyl, and C₁-C₈alkyl, C₂-C₈alkenyl, and C₂-C₈alkynyl, wherein in each C₁-C₈alkyl, C₂-C₈alkenyl, and C₂-C₈alkynyl, in the definition of R¹¹ one or more carbon atoms is optionally replaced by O, NR¹⁰, —C(O)—, —C(O)O—, —S(O)nNR¹⁰, —NR¹⁰S(O)n-, —NR¹⁰C(O)NR¹⁰, OC(O), —S(O)n-, —C(O)NR¹⁰—, or —NR¹⁰C(O)— where n is 0, 1, or 2, and in which each C₀-C₄alkyl, C₁-C₈alkyl, C₂-C₈alkenyl, or C₂-C₈alkynyl is optionally substituted with one or more substituents R¹³.

R¹² is selected from —C₀-C₄alkyl(C₃-C₇cycloalkyl), —O—C₀-C₄alkyl(C₃-C₇cycloalkyl), —C₀-C₄alkyl(aryl), —O—C₀-C₄alkyl(aryl), —C₀-C₄alkyl(5- to 6-membered heteroaryl), —O—C₀-C₄alkyl(5- to 6-membered heteroaryl), —C₀-C₄alkyl(3- to 6-membered heterocycloalkyl), and —O—C₀-C₄alkyl(3- to 6-membered heterocycloalkyl), each of which is optionally substituted with one or more substituents independently chosen from halogen, hydroxyl, amino, nitro, cyano, —CHO, —COOH, oxo, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₆alkyl, C₁-C₆alkoxy, C₁-C₆alkylester, —C₀-C₄alkyl(mono- or di-C₁-C₆alkylamino), C₂-C₆alkanoyl, C₂-C₆alkenyl, and C₂-C₆alkynyl.

R¹³ is independently chosen at each occurrence from halogen, hydroxyl, amino, nitro, cyano, —CHO, —COOH, oxo, C₃-C₇cycloalkyl, and phenyl.

In Formula I the following provisos apply.

When (i) X¹ and X² are both N, Z is O, R¹ is methyl, and R³ is hydrogen, R² is not unsubstituted phenyl; and (i) When: X¹ and X² are both N, Z is O, and R¹ is hydrogen, R² is not naphthyl, 3,4-di-chloro-phenyl, 4-methyl-phenyl, 3,4-dimethyl-phenyl, or 3-Cl,4-methyl-phenyl when R³ is hydrogen.

(ii) When: X¹ and X² are both N, Z is O, and R¹ is hydrogen, R² is not 4-nitro-phenyl, when R³ is methyl.

(iii) When: X¹ and X² are both N, Z is O, and R¹ is hydrogen, R² is not 3,4-di-chloro-phenyl, when R³ is naphthyl.

(iv) When: X¹ and X² are both N, Z is O, and R¹ is hydrogen, R² is not 3,4-di-chloro-phenyl, when R³ is 3,4-di-chloro-phenyl.

Formula I also includes subformulae in which the variables carry any of the following definitions. Any of the variable definitions below can be combined so long as a stable compound results.

X¹ and X² can both be nitrogen.

One of X¹ and X² can be nitrogen and the other can be carbon.

The disclosure includes Formula I-A, I-B, and I-C.

The R¹ Variable

R¹ may carry the following definitions.

(i) R¹ is hydrogen or unsubstituted C₁-C₆alkyl.

(ii) R¹ is hydrogen.

The R² Variable

R² may carry the following definitions.

(i) R² is C₁-C₈alkyl, C₂-C₈alkenyl, or C₂-C₈alkynyl; in each C₀-C₄alkyl, C₁-C₈alkyl, C₂-C₈alkenyl, or C₂-C₈alkynyl one or more carbon atoms is optionally replaced by O, NR¹⁰, —C(O)—, —C(O)O—, —OC(O), —S(O)n—, —C(O)NR¹⁰—, or —NR¹⁰C(O)— where n is 0, 1, or 2, and in which the C₀-C₄alkyl, C₁-C₈ alkyl, C₂-C₈alkenyl, or C₂-C₈alkynyl is optionally substituted with one or more substituents R¹³.

(ii) R² is C₁-C₈alkyl, optionally substituted with one or more substituents independently chosen from halogen, hydroxyl, amino, nitro, cyano, and oxo.

(iii) R² is —C₀-C₄alkyl(C₃-C₇cycloalkyl), —C₀-C₄alkyl(bridged C₇-C₁₂cycloalkyl), —C₀-C₄alkyl(aryl), —C₀-C₄alkyl(mono- or bi-cyclic heteroaryl), or —C₀-C₄alkyl(4- to 7-membered heterocycloalkyl), each of which is optionally substituted with one or more substituents independently chosen from R¹¹ and 0 or 1 substituents R¹²; in each C₀-C₄alkyl, C₁-C₈alkyl, C₂-C₈alkenyl, or C₂-C₈alkynyl one or more carbon atoms is optionally replaced by O, NR¹⁰, —C(O)—, —C(O)O—, —OC(O), —S(O)n—, —C(O)NR¹⁰—, or —NR¹⁰C(O)— where n is 0, 1, or 2, and in which the C₀-C₄alkyl, C₁-C₈ alkyl, C₂-C₈alkenyl, or C₂-C₈alkynyl is optionally substituted with one or more substituents R¹³.

(iv) R² is —C₀-C₄alkyl(bridged C₇-C₁₂cycloalkyl) or —C₀-C₄alkyl(aryl), each of which is optionally substituted with one or more substituents independently chosen from R¹¹ and 0 or 1 substituents R¹²; in C₀-C₄alkyl one or more carbon atoms is optionally replaced by O, NR¹⁰, —C(O)—, —C(O)O—, —OC(O), —S(O)n—, —C(O)NR¹⁰—, or —NR¹⁰C(O)— where n is 0, 1, or 2, and in which the C₀-C₄alkyl is optionally substituted by R¹³.

(v) R² is C₀-C₂alkyl(bridged C₇-C₁₂cycloalkyl), which is optionally substituted with one or more substituents independently chosen from R¹¹.

(vi) R² is adamantan-1-yl or —CH₂(adamantan-1-yl), each of which is unsubstituted or substituted with halogen, hydroxyl, amino, nitro, cyano, C₁-C₄alkyl, C₁-C₄alkoxy, —C₀-C₂alkyl(mono- or di-C₁-C₄alkylamino), C₁-C₂haloalkyl, and C₁-C₂haloalkoxy.

(vii) R² is —C₀-C₄alkyl(phenyl), naphthyl, benzo[d][1,3]dioxolyl, or fluorenyl, or fluorenyl, each of which is optionally substituted with one or more substituents independently chosen from R¹¹ and 0 or 1 substituents R¹²; in C₀-C₄alkyl one or more carbon atoms is optionally replaced by 0, NR¹⁰, —C(O)—, —C(O)O—,

—OC(O), —S(O)n-, —S(O)nNR¹⁰, —NR¹⁰S(O)n-, —NR¹⁰C(O)NR¹⁰, —C(O)NR¹⁰—, or —NR¹⁰C(O)— where n is 0, 1, or 2, and in which the C₀-C₄alkyl is optionally substituted by R¹³.

(viii) R² is phenyl, which is optionally substituted by one or more substituents independently chosen from R¹¹.

(ix) R² is phenyl, which is optionally substituted by one or more substituents independently chosen from halogen, hydroxyl, amino, nitro, cyano, oxo, halosulfanyl, and C₁-C₈alkyl, C₂-C₈alkenyl, and C₂-C₈alkynyl, wherein in each C₁-C₈alkyl, C₂-C₈alkenyl, and C₂-C₈alkynyl, in the definition of R¹¹ one or more carbon atoms is optionally replaced by O, NR¹⁰, —C(O)O—, —OC(O), or —S(O)n-, where n is 0, 1, or 2, and in which each C₁-C₈alkyl, C₂-C₈alkenyl, or C₂-C₈alkynyl is optionally substituted with one or more substituents R¹³.

(x) R² is —C₀-C₄alkyl(phenyl), which is optionally substituted with one or more substituents independently chosen from R¹¹ and 0 or 1 substituents R¹²; in C₀-C₄alkyl one or more carbon atoms is optionally replaced by O, NR¹⁰, —C(O)—, —C(O)O—, —OC(O), —S(O)n-, —C(O)NR¹⁰—, or —NR¹⁰C(O)-where n is 0, 1, or 2, and in which the C₀-C₄alkyl is optionally substituted by R¹³;

R¹² is selected from —C₀-C₄alkyl(C₃-C₇cycloalkyl), —O—C₀-C₄alkyl(C₃-C₇cycloalkyl), —C₀-C₄alkyl(phenyl), —O—C₀-C₄alkyl(phenyl), —C₀-C₄alkyl(5- to 6-membered heteroaryl), —O—C₀-C₄alkyl(5- to 6-membered heteroaryl), each of which is optionally substituted with one or more substituents independently chosen from halogen, hydroxyl, amino, nitro, cyano, —CHO, —COOH, oxo, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₆alkyl, C₁-C₆alkoxy, C₁-C₆alkylester, —C₀-C₄alkyl(mono- or di-C₁-C₆alkylamino), C₂-C₆alkanoyl, C₂-C₆alkenyl, and C₂-C₆alkynyl.

The R³ Variable

R³ may carry any of the following definitions.

(i) R³ is hydrogen.

(ii) R³ is C₁-C₈alkyl, C₂-C₈alkenyl, or C₂-C₈alkynyl,

In C₁-C₈alkyl, C₂-C₈alkenyl, or C₂-C₈alkynyl one or more carbon atoms is optionally replaced by O, NR¹⁰, C(O)O—, —OC(O), or —S(O)n-, where n is 0, 1, or 2, and in which the C₁-C₈ alkyl, C₂-C₈alkenyl, or C₂-C₈alkynyl is optionally substituted with one or more substituents R¹³.

(iii) R³ is C₁-C₆alkyl optionally substituted with hydroxyl.

(iv) R³ is —C₀-C₄alkyl(C₃-C₇cycloalkyl) or —C₀-C₄alkyl(aryl), which is optionally substituted with one or more independently chosen R¹¹ substituents.

In an embodiment, the disclosure includes a compound or salt of Formula I in which the variables carry the following definitions.

X¹ and X² are C or N, with at least one of X¹ and X² being N; it is preferred that both X¹ and X² are N.

Z is O.

R¹ is hydrogen or C₁-C₂alkyl.

R² is C₁-C₈alkyl, C₂-C₈alkenyl, or C₂-C₈alkynyl; or

R² is —C₀-C₄alkyl(C₃-C₇cycloalkyl), —C₀-C₄alkyl(bridged C₇-C₁₂cycloalkyl), —C₀-C₄alkyl(aryl), —C₀-C₄alkyl(mono- or bi-cyclic heteroaryl), or —C₀-C₄alkyl(4- to 7-membered heterocycloalkyl), each of which is optionally substituted with one or more substituents independently chosen from R¹¹ and 0 or 1 substituents R¹².

R³ is H or C₁-C₆alkyl optionally substituted with hydroxyl;

wherein in each C₀-C₄alkyl, C₁-C₈alkyl, C₂-C₈alkenyl, or C₂-C₈alkynyl in the definitions of R² one or more carbon atoms is optionally replaced by O, NR¹⁰, —C(O)O—, —OC(O), or —S(O)n-, where n is 0, 1, or 2, and in which the C₀-C₄alkyl, C₁-C₈ alkyl, C₂-C₈alkenyl, or C₂-C₈alkynyl is optionally substituted with one or more substituents R¹³.

R¹⁰ is independently chosen at each occurrence from hydrogen, C₁-C₆alkyl, and —C₀-C₂alkyl(C₃-C₇cycloalkyl).

R¹¹ is independently selected at each occurrence from halogen, hydroxyl, amino, nitro, cyano, —CHO, —COOH, oxo, halosulfanyl, and C₁-C₈alkyl, C₂-C₈alkenyl, and C₂-C₈alkynyl, wherein in each C₁-C₈alkyl, C₂-C₈alkenyl, and C₂-C₈alkynyl, in the definition of R¹¹ one or more carbon atoms is optionally replaced by O, NR¹⁰, —C(O)O—, —OC(O), or —S(O)n-, where n is 0, 1, or 2, and in which each C₁-C₈alkyl, C₂-C₈alkenyl, or C₂-C₈alkynyl is optionally substituted with one or more substituents R¹³.

R¹² is selected from —C₀-C₄alkyl(C₃-C₇cycloalkyl), —O—C₀-C₄alkyl(C₃-C₇cycloalkyl), —C₀-C₄alkyl(aryl), —O—C₀-C₄alkyl(aryl), —C₀-C₄alkyl(5- to 6-membered heteroaryl), —O—C₀-C₄alkyl(5- to 6-membered heteroaryl), —C₀-C₄alkyl(3- to 6-membered heterocycloalkyl), and —O—C₀-C₄alkyl(3- to 6-membered heterocycloalkyl), each of which is optionally substituted with one or more substituents independently chosen from halogen, hydroxyl, amino, nitro, cyano, —CHO, —COOH, oxo, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₆alkyl, C₁-C₆alkoxy, C₁-C₆alkylester, —C₀-C₄alkyl(mono- or di-C₁-C₆alkylamino), C₂-C₆alkanoyl, C₂-C₆alkenyl, and C₂-C₆alkynyl.

R¹³ is independently chosen at each occurrence from halogen, hydroxyl, amino, nitro, cyano, —CHO, —COOH, oxo, C₃-C₇cycloalkyl, and phenyl.

Processes for preparing compounds of a formula of the disclosure or for preparing intermediates useful for preparing compounds of Formula A, Formula I or other formulas of the disclosure are provided as further embodiments. Intermediates useful for preparing compounds of Formula A, Formula I, or other formulas are also provided as further embodiments of the disclosure.

Pharmaceutical Compositions

The disclosure includes a pharmaceutical composition comprising a compound or salt thereof of the disclosure, together with a pharmaceutically acceptable excipient.

This disclosure provides pharmaceutical compositions comprising compounds of the Formula A and Formula I. The pharmaceutical composition may comprise one or more compounds of the disclosure and pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier. In one embodiment, the compounds are administered as a pharmaceutical composition.

The route of administration can vary depending on the type of compound being administered. In one aspect, the compounds are administered via routes such as oral, topical, rectal, intramuscular, intramucosal, intranasal, inhalation, ophthalmic, and intravenous.

The present disclosure further provides for administration of a compound of Formula A and Formula I as an immediate release or as a controlled-release formulation.

The dosage of the active compound(s) being administered will depend on the condition being treated, the particular compound, and other clinical factors such as age, sex, weight, and health of the subject being treated, the route of administration of the compound(s), and the type of composition being administered (tablet, gel cap, capsule, solution, suspension, inhaler, aerosol, elixir, lozenge, injection, patch, ointment, cream, etc.). It is to be understood that the present disclosure has application for both human and veterinary use.

Processes for preparing compounds of any of the formulas of the disclosure or for preparing intermediates useful for preparing compounds of any of the formulas of the disclosure are provided as further embodiments. Intermediates useful for preparing compounds of Formula A and Formula I are also provided as further embodiments of the disclosure.

Processes for preparing compounds of any of the formulas of the disclosure are provided as further embodiments of the disclosure and are illustrated by the following procedures in which the meanings of the generic radicals are as given above unless otherwise qualified.

In one embodiment, compounds of the disclosure may be systemically administered, e.g., orally, in combination with a pharmaceutically acceptable carrier such as an inert diluent or an assimilable edible carrier. They may be enclosed in hard or soft shell gelatin capsules, may be compressed into tablets, or may be incorporated directly with the food of the patient's diet. For oral therapeutic administration, the active compound may be combined with one or more excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like. Such compositions and preparations should contain at least 0.1% of active compound. The percentage of the compositions and preparations may, of course, be varied and may conveniently be between about 2 to about 60% of the weight of a given unit dosage form. The amount of active compound in such therapeutically useful compositions is such that an effective dosage level will be obtained.

The tablets, troches, pills, capsules, and the like may also contain the following: binders such as gum tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid and the like; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, fructose, lactose or aspartame or a flavoring agent such as peppermint, oil of wintergreen, or cherry flavoring may be added. When the unit dosage form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier, such as a vegetable oil or a polyethylene glycol. Various other materials may be present as coatings or to otherwise modify the physical form of the solid unit dosage form. For instance, tablets, pills, or capsules may be coated with gelatin, wax, shellac or sugar and the like. A syrup or elixir may contain the active compound, sucrose or fructose as a sweetening agent, methyl and propylparabens as preservatives, a dye and flavoring such as cherry or orange flavor. Of course, any material used in preparing any unit dosage form should be pharmaceutically acceptable and substantially non-toxic in the amounts employed. In addition, the active compound may be incorporated into sustained-release preparations and devices.

The active compound may also be administered intravenously or intraperitoneally by infusion or injection. Solutions of the active compound or its salts can be prepared in water, optionally mixed with a nontoxic surfactant. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, triacetin, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.

The pharmaceutical dosage forms suitable for injection or infusion can include sterile aqueous solutions or dispersions or sterile powders comprising the active ingredient which are adapted for the extemporaneous preparation of sterile injectable or infusible solutions or dispersions, optionally encapsulated in liposomes. In all cases, the ultimate dosage form should be sterile, fluid and stable under the conditions of manufacture and storage. The liquid carrier or vehicle can be a solvent or liquid dispersion medium comprising, for example, water, ethanol, a polyol (for example, glycerol, propylene glycol, liquid polyethylene glycols, and the like), vegetable oils, nontoxic glyceryl esters, and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the formation of liposomes, by the maintenance of the required particle size in the case of dispersions or by the use of surfactants. The prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars, buffers or sodium chloride. Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminum monostearate, and gelatin.

Sterile injectable solutions are prepared by incorporating the active compound in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filter sterilization. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and the freeze-drying techniques, which yield a powder of the active ingredient plus any additional desired ingredient present in the previously sterile-filtered solutions.

For topical administration, the present compounds may be applied in pure form, i.e., when they are liquids. However, it will generally be desirable to administer them to the skin as compositions or formulations, in combination with a dermatologically acceptable carrier, which may be a solid or a liquid.

Useful solid carriers include finely divided solids such as talc, clay, microcrystalline cellulose, silica, alumina and the like. Useful liquid carriers include water, alcohols or glycols or water-alcohol/glycol blends, in which the present compounds can be dissolved or dispersed at effective levels, optionally with the aid of non-toxic surfactants. Adjuvants such as fragrances and additional antimicrobial agents can be added to optimize the properties for a given use. The resultant liquid compositions can be applied from absorbent pads, used to impregnate bandages and other dressings, or sprayed onto the affected area using pump-type or aerosol sprayers. Thickeners such as synthetic polymers, fatty acids, fatty acid salts and esters, fatty alcohols, modified celluloses or modified mineral materials can also be employed with liquid carriers to form spreadable pastes, gels, ointments, soaps, and the like, for application directly to the skin of the user.

Examples of useful dermatological compositions which can be used to deliver the compounds of Formula A or Formula I to the skin are known to the art; for example, see Jacquet et al. (U.S. Pat. No. 4,608,392), Geria (U.S. Pat. No. 4,992,478), Smith et al. (U.S. Pat. No. 4,559,157) and Wortzman (U.S. Pat. No. 4,820,508). Useful dosages of the compounds of the disclosure can be determined by comparing their in vitro activity, and in vivo activity in animal models. Methods for the extrapolation of effective dosages in mice, and other animals, to humans are known to the art; for example, see U.S. Pat. No. 4,938,949.

Generally, the concentration of the compound(s) of the disclosure in a liquid composition, such as a lotion, will be from about 0.1-25 wt-%, preferably from about 0.5-10 wt-%. The concentration in a semi-solid or solid composition such as a gel or a powder will be about 0.1-5 wt-%, preferably about 0.5-2.5 wt-%. The amount of the compound, or an active salt or derivative thereof, required for use in treatment will vary not only with the particular salt selected but also with the route of administration, the nature of the condition being treated and the age and condition of the patient and will be ultimately at the discretion of the attendant physician or clinician.

For example, in one embodiment relating to oral administration to humans, a dosage of between approximately 0.1 and 300 mg/kg/day, or between approximately 0.5 and 50 mg/kg/day, or between approximately 1 and 10 mg/kg/day, is generally sufficient, but will vary depending on such things as the disorder being treated, the length of treatment, the age, sex, weight, and/or health of the subject, etc. In one aspect, a unit dose is used. In one aspect, the unit dose is supplied in a syringe. The combinations of drugs can be administered in formulations that contain all drugs being used, or the drugs can be administered separately. In some cases, it is anticipated that multiple doses/times of administration will be required or useful. Additionally, for some treatment regimens, at least two compounds will be used. In one aspect, at least three compounds will be administered. The present disclosure further provides for varying the length of time of treatment.

In general, however, a suitable dose will be in the range of from about 0.5 to about 100 mg/kg, e.g., from about 10 to about 75 mg/kg of body weight per day, such as 3 to about 50 mg per kilogram body weight of the recipient per day, preferably in the range of 6 to 90 mg/kg/day, most preferably in the range of 15 to 60 mg/kg/day.

The compound is conveniently administered in unit dosage form; for example, containing 5 to 1000 mg, conveniently 10 to 750 mg, most conveniently, 50 to 500 mg of active ingredient per unit dosage form.

Ideally, when the active ingredient needs to enter circulation and be delivered via blood, the active ingredient, in one embodiment, should be administered to achieve peak plasma concentrations of the active compound of from about 0.5 to about 75 μM, preferably, about 1 to 50 μM, most preferably, about 2 to about 30 μM. This may be achieved, for example, by the intravenous injection of a 0.05 to 5% solution of the active ingredient, optionally in saline, or orally administered as a bolus containing about 1-100 mg of the active ingredient. Desirable blood levels may be maintained by continuous infusion to provide about 0.01-5.0 mg/kg/hr or by intermittent infusions containing about 0.4-15 mg/kg of the active ingredient(s).

The desired dose may conveniently be presented in a single dose or as divided doses administered at appropriate intervals, for example, as two, three, four or more sub-doses per day. The sub-dose itself may be further divided, e.g., into a number of discrete loosely spaced administrations; such as multiple inhalations from an insufflator or by application of a plurality of drops into the eye.

Pharmaceutical compositions of the disclosure can further comprise additional therapeutic additives, alone or in combination (e.g., 2, 3, or 4 additional additives). Examples of additional additives include but are not limited to: (a) antimicrobials, (b) steroids (e.g., hydrocortisone, triamcinolone); (c) pain medications (e.g., aspirin, an NSAID, and a local anesthetic); (d) anti-inflammatory agents; and (e) combinations thereof. Non-synthetic matrix proteins like collagen, glycosaminoglycans, and hyaluronic acid, which are enzymatically digested in the body, are useful for delivery (see U.S. Pat. Nos. 4,394,320; 4,472,840; 5,366,509; 5,606,019; 5,645,591; and 5,683,459) and are suitable for use with the present disclosure. Other implantable media and devices can be used for delivery of the compounds of the disclosure in vivo. These include, but are not limited to, sponges, such as those from Integra, fibrin gels, scaffolds formed from sintered microspheres of polylactic acid glycolic acid copolymers (PLAGA), and nanofibers formed from native collagen, as well as other proteins. The compounds of the present disclosure can be further combined with growth factors, nutrient factors, pharmaceuticals, calcium-containing compounds, anti-inflammatory agents, antimicrobial agents, or any other substance capable of expediting or facilitating bone or tissue growth, stability, and remodeling.

The compositions of this disclosure can also be combined with inorganic fillers or particles. For example for use in implantable grafts the inorganic fillers or particles can be selected from hydroxyapatite, tri-calcium phosphate, ceramic glass, amorphous calcium phosphate, porous ceramic particles or powders, mesh titanium or titanium alloy, or particulate titanium or titanium alloy.

Examples of other antimicrobial agents that can be used in the present disclosure include, but are not limited to, isoniazid, ethambutol, pyrazinamide, streptomycin, clofazimine, rifabutin, fluoroquinolones, ofloxacin, sparfloxacin, rifampin, azithromycin, clarithromycin, dapsone, tetracycline, erythromycin, cikprofloxacin, doxycycline, ampicillin, amphotericine B, ketoconazole, fluconazole, pyrimethamine, sulfadiazine, clindamycin, lincomycin, pentamidine, atovaquone, paromomycin, diclarazaril, acyclovir, trifluorouridine, foscarnet, penicillin, gentamicin, ganciclovir, iatroconazole, miconazole, Zn-pyrithione, and silver salts, such as chloride, bromide, iodide, and periodate.

In one embodiment, the compounds of the disclosure can first be encapsulated into microcapsules, microspheres, microparticles, microfibers, reinforcing fibers and the like to facilitate mixing and achieving controlled, extended, delayed and/or sustainedrelease and combined other agents or drugs. Encapsulating the biologically active agent can also protect the agent against degradation during formation of the composite of the disclosure.

In another embodiment of the disclosure, the compound is controllably released into a subject when the composition of the disclosure is implanted into a subject, due to bioresorption relying on the time scale resulting from cellular remodeling. In one aspect, the composition may be used to replace an area of discontinuity in the tissue. The area of discontinuity can be the result of trauma, a disease, disorder, or condition, surgery, injury, etc.

As used herein, an “instructional material” includes a publication, a recording, a diagram, or any other medium of expression which can be used to communicate the usefulness of the composition of the disclosure for its designated use. The instructional material of the kit of the disclosure may, for example, be affixed to a container which contains the composition or be shipped together with a container which contains the composition. Alternatively, the instructional material may be shipped separately from the container with the intention that the instructional material and the composition be used cooperatively by the recipient.

The method of the disclosure includes a kit comprising a compound identified in the disclosure and an instructional material which describes administering the compound or a composition comprising the compound to a subject. This should be construed to include other embodiments of kits that are known to those skilled in the art, such as a kit comprising a (preferably sterile) solvent suitable for dissolving or suspending the composition of the disclosure prior to administering the compound to a subject. Preferably the subject is a human.

In accordance with the present disclosure, as described above or as discussed in the Examples below, there can be employed conventional chemical, cellular, histochemical, biochemical, molecular biology, microbiology, and in vivo techniques which are known to those of skill in the art. Such techniques are explained fully in the literature.

Without further description, it is believed that one of ordinary skill in the art can, using the preceding description and the following illustrative examples, make and utilize the compounds of the present disclosure.

Methods of Treatment

Mitochondria regulate cellular metabolism and play an important role in the pathogenesis of some of the most prevalent human diseases including obesity, cancer, diabetes, neurodegeneration, and heart disease. The compounds of the disclosure, including are useful for treating and preventing these diseases and disorders and others described herein, as well as others where a mitochondrial uncoupler is useful.

Many anti-diabetes drugs such as insulin-sensitizers promote glucose clearance from the blood by effectively ‘pushing’ glucose into nutrient overloaded tissues; however, in contrast to this approach our strategy is aimed at reducing cellular nutrient stores so that tissues will ‘pull’ glucose from the circulation. The present method is modeled after exercise and calorie restriction interventions which also reduce cellular nutrient stores to improve glycemia and insulin sensitivity. The proof of principle is validated in humans treated with the mitochondrial uncoupler 2,4-dinitrophenol (DNP). DNP decreases adiposity and improves metabolism in humans; however, it also has a very narrow therapeutic window and was removed from FDA approval in 1938. Other anti-diabetes drugs including agonists of thyroid hormone and inhibitors of 11-β hydroxysteroid dehydrogenase type 1 have off-target effects of increased energy expenditure that may mediate some of the protective effects of these compounds. Nevertheless, there are no drugs have been specifically targeted for increased energy expenditure.

In one embodiment, a compound of the disclosure is useful for treating disease, disorders, and conditions which are associated with defects in mitochondrial function or which can be treated with drugs or agents that act as uncoupling agents. The methods can comprise administering to a subject in need thereof a pharmaceutical composition comprising an effective amount of compound of Formula A or Formula I, or a salt thereof as a first therapeutic agent, together with a pharmaceutically acceptable carrier, and optionally with at least one additional therapeutic agent.

In one embodiment, the present disclosure provides compositions and methods for increasing oxygen consumption, decreasing cellular reactive oxygen species, depolarizing a mitochondrial inner membrane, and increasing oxygen consumption rate without donating electrons to the electron transport chain using a mitochondrial uncoupler, said method comprising contacting a cell or mitochondria with a composition comprising at least one compound of the disclosure and optionally an additional therapeutic agent.

For example, it is disclosed herein that the mitochondrial uncoupling agents of this disclosure both prevent and reverse body fat mass increases in mice fed a high fat and high sugar Western diet. Apart from body fat, the mitochondrial uncoupling agents decrease insulin levels, which is important because it corrects hyperinsulinemia, improves glucose tolerance, and protect against diet-induced glucose tolerance. It is also disclosed herein that administration of the mitochondrial uncoupling agents reverses insulin resistance, including diet-induced insulin resistance, and restores insulin sensitivity index. Therefore, the compounds of the disclosure are useful for preventing and treating diabetes. It is also disclosed that compounds of the disclosure decrease liver fat, thus providing a treatment for fatty liver disease. It is disclosed herein that a compound of the disclosure can prevent weight gain without altering food intake and can prevent diet-induced fat accumulation. Compounds of the disclosure are also useful for reversing diet-induced weight or fat gain and can reverse diet-induced fat gain and fatty liver.

Reactive oxygen species generated during respiration contribute to biological damage over time, causing mutations and other biological changes that lead to cancer, aging, and decreased lifespan. Mitochondrial uncoupling decreases the production of reactive oxygen species, potentially lowering the risk of cancer, decreasing the effects of aging, and increasing lifespan. Mitochondrial uncouplers reverse or interfere with many aspects of cancer metabolism and are therefore effective in a broad range of cancer types. For example, mitochondrial uncouplers are effective in treatment of cancers with impaired p53 expression or activity (https://www.nature.com/articles/s41467-018-05805-1) such as certain breast and ovarian cancers, Ras mutant cancers (https://www.cell.com/molecular-cell/pdf/S1097-2765(15)00004-0.pdf), and/or beta-catenin mutant cancers (https://www.ncbi.nlm.nih.gov/pubmed/28107588). Mitochondrial uncouplers are demonstrated to treat adrenocortical carcinoma (http://clincancerres.aacrjournals.org/content/clincanres/early/2016/02/12/1078-0432.CCR-15-2256.full.pdf) melanoma (https://www.ncbi.nlm nih.gov/pmc/articles/PMC5833689/), primary colon cancer (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6056247/) and metastasis to distant organs including the liver (https://www.nature.com/articles/s41419-017-0092-6).

A compound of the disclosure may exhibit at least one of the following properties or activities: energy expenditure agonist, mitochondrial uncoupler, antioxidant, increases oxygen consumption, depolarizes the mitochondrial inner membrane, stimulates respiration in isolated mitochondria, increases or stimulates oxygen consumption without donating electrons to the electron transport chain, lacks protonophore activity at the plasma membrane, decreases reperfusion-induced mitochondrial oxidative stress, decreases cellular reactive oxygen species, improves glucose tolerance, provides protection from high fat induce glucose tolerance, activates AMPK without depletion of ATP, prevents, reverses or treats insulin resistance, prevents, reverses or treats hyperinsulinemia, prevents, reverses or treats hyperlipidemia, improves blood lipid profiles, improves leanness, improves insulin sensitivity, protects from ischemic-reperfusion injury, and is less toxic than other mitochondrial inhibitors. In one embodiment, a compound of the disclosure has two or more of these properties. In one embodiment, a compound of the disclosure has three or more of these properties. In one embodiment, a compound of the disclosure has four, five, six, seven, eight, nine, ten, eleven, twelve, or more of these properties. In one embodiment, a compound of the disclosure has one, two, three, four, five, six, seven, eight, nine, or ten of these properties.

Compounds of the disclosure can be administered to a subject at various times, dosages, and more than once, depending on, for example, the age, sex, health, and weight of the subject, as well as on the particular disease, disorder, or condition to be treated or prevented. In one aspect, a compound is administered at a dosage ranging from about 0.1 mg/kg to about 500 mg/kg body weight. In another aspect, the compound is administered at a dosage ranging from about 0.5 mg/kg to about 100 mg/kg body weight or about 0.5 mg/kg to about 25 mg/kg body weight. In yet another aspect, the compound is administered at a dosage ranging from about 1.0 mg/kg to about 50 mg/kg body weight. In one aspect, about 3.0 mg/kg is administered. In another aspect, about 5.0 mg/kg is administered. In one aspect, the dose is selected from 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 2.0, 3.0, 4.0, 5.0, 6.0, 7.0, 8.0, 9.0, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 300, 400, and 500 mg/kg body weight, as well as all fractions, decimals, and integers in the range of numbers listed. In another aspect, the compound is administered as a unit dose ranging from about 10 mg to about 500 mg/unit dose.

In one aspect, a compound is administered to a subject more than once. In one aspect, the compound is a mitochondrial protonophore uncoupler lacking protonophore activity at the plasma membrane.

In one aspect the disclosure provides a method of treating or preventing a condition responsive to mitochondrial uncoupling, comprising administering a therapeutically effective amount of a compound Formula A or Formula I or salt thereof to a patient in need of such treatment.

In one aspect, the disease, disorder or condition associated with a defect in mitochondria function is selected from the group consisting of obesity, ischemia reperfusion injury, hyperinsulinemia, hyperlipidemia, glycemia, glucose tolerance, insulin sensitivity, adiposity, insulin resistance, obesity, diabetes, cancer, neurodegeneration, heart disease, renal disease, heart failure, Parkinson's disease, traumatic brain injury, stroke, aging, and disorders standing to benefit from increased energy expenditure. In one aspect, the compound is a mitochondrial uncoupler.

In one aspect the condition responsive to mitochondrial uncoupling is obesity, type II diabetes, fatty liver disease, insulin resistance, multiple sclerosis, cancer, Huntington's disease, Alzheimer's dementia, Parkinson's disease, ischemia reperfusion injury, heart failure, non-alcoholic fatty liver disease (NALFD), or non-alcoholic steatohepatitis (NASH).

The disclosure includes a method of regulating glucose homeostasis or insulin action in a patient comprising administering a therapeutically effective amount of a compound or salt of any one of Formula A or Formula I to the patient.

The disclosure includes a method of treating hyperlipidemia, glycemia, glucose tolerance, insulin sensitivity, adiposity, insulin resistance, obesity, or diabetes in a patient comprising administering a therapeutically effective amount of a compound of Formula A or Formula I to the patient.

One of ordinary skill in the art will appreciate that not all configurations need to be effective or as effective as other compounds of the genus based on the teachings disclosed herein.

The disclosure is now described with reference to the following Examples and Embodiments. Without further description, it is believed that one of ordinary skill in the art can, using the preceding description and the following illustrative examples, make and utilize the present disclosure and practice the claimed methods. The following working examples therefore, are provided for the purpose of illustration only and specifically point out the preferred embodiments of the present disclosure, and are not to be construed as limiting in any way the remainder of the disclosure. Therefore, the examples should be construed to encompass any and all variations which become evident as a result of the teaching provided herein.

EXAMPLES General Methods

The following starting materials and general procedures are used in synthetic examples that follow.

In all synthetic examples room temperature (rt) is about 21° C.

NMR Solvent Reference:^(i) (CD₃)₂CO (2.05/29.84 ppm); (CD₃)₂SO (2.50/39.52 ppm).

NMR Abbreviations: aq.=aqueous, app=apparent, br=broad, s=singlet, d=doublet, t=triplet, q=quartet, p=pentet.*means rotamers.

Synthesis of Starting Material Example 1. Synthesis of [1,2,5]Oxadiazolo[3,4-b]pyrazine-5,6-diol (1-1)

In a 500 mL round-bottom flask equipped with a condenser, a mixture of 1,2,5-oxadiazole-3,4-diamine (50.0 g, 500 mmol) and oxalic acid (49.6 g, 551 mmol) in aq. HCl (250 mL, 10% v/v) was heated in a sand bath to reflux for 4 h. The resulting mixture was allowed to cool in an ice bath and the precipitate was filtered, rinsed with water (20 mL) and then ether (2×150 mL), and collected to yield 1-1 (55.2 g, 72%) as a colorless solid: ¹H NMR ((CD₃)₂CO, 400 MHz) δ 11.65 (br s, 2H); ¹³C NMR ((CD₃)₂CO, 100 MHz) δ 153.9, 144.8.

Example 2. Synthesis of 5,6-Dichloro-[1,2,5]oxadiazolo[3,4-b]pyrazine (1-2)

In a 500 mL two-neck round-bottom flask equipped with a glass stopper and a condenser connected to an aq. Na₂CO₃ trap, a mixture of diol 1-1 (37.0 g, 240 mmol) and PCI₅ (120 g, 576 mmol) in POCl₃ (45 mL) was heated to 95° C. for 2 h. The mixture was allowed to cool to rt and then to 5-10° C. in an ice bath. The reaction mixture was slowly poured onto ice cold water (3×250 mL beakers with 100 mL H₂O each), not allowing the temperature of the water to rise above 25° C. (monitored by thermometer in the water bath). The colorless precipitate was filtered, rinsed with water, and dissolved in acetone (ca. 200 mL). Water (3× volume of acetone) was added to the organic solution to promote precipitation and the colorless solid was filtered, collected, and dried under vacuum with P205 as a desiccant to yield 1-2 (35.1 g, 77%) as a colorless solid: ¹³C NMR ((CD₃)₂CO₃ 100 MHz) δ 155.9, 151.9.

Large scale synthesis of starting materials 1-1 and 1-2 is shown in Scheme 1.

General Procedures General Procedures for the Preparation of Compounds by Nucleophilic Aromatic Substitution

General Procedure 1-A. In a screw-cap vial or round-bottom flask, the requisite amine (0.70-0.98 mmol) was added to a stirring mixture of dichloro 1-2 (0.200 g, 1.05 mmol) in anhydrous THF (or acetone where indicated) (0.1-0.2 M). Then, Et₃N (0.15 mL, 1.1 mmol or 2.2 mmol when an amine salt is used) was added and the resulting dark mixture was stirred at room temperature (unless otherwise indicated) for 2-20 h. The mixture was diluted with an aqueous solution of KOH (6 equiv.) and stirring was continued for 30 min-2 h. The mixture was acidified with 1 M HCl and extracted with EtOAc. The organic layer was washed with brine, dried (Na₂SO₄), and concentrated to a residue. The residue was purified by chromatography on SiO₂ using a MeOH/CH₂Cl₂ or EtOAc/hexanes solvent system to yield the desired product. When additional purification was needed, the solid was dissolved in a minimal amount of hot acetone, allowed to cool to room temperature, and precipitated by the addition of hexanes. The precipitate was filtered, rinsed with hexanes, and collected to yield the desired product.

General Procedure 1-B. To a round bottom flask containing a stir bar was added dichloro 1-2 (1.05 mmol) which was diluted with anhydrous THF (4 mL), followed by the amine (0.838 mmol, 0.8 equiv.). The resulting solution was stirred at 50° C. for 16 h. KOH (6.28 mmol, 6.0 equiv.) in H₂O (8 mL) and THF (2 mL) was added and stirring was continued for an additional 1 h. The mixture was then acidified with 10% aqueous HCl and extracted with EtOAc. The organic layer was washed with brine, dried (Na₂SO₄), and concentrated to a solid. The solid was purified by chromatography on SiO₂ using a MeOH/CH₂Cl₂ to yield the desired compound, a 6-amino-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-ol.

Scheme 2 illustrates general procedures 1-A and 1-B

General Procedure 1-C. 5-Chloro-6-alkoxy-[1,2,5]oxadiazolo[3,4-b]pyrazine was taken and dissolved in anhydrous THF (0.1 M-0.2 M) and added to a sealed tube under argon atmosphere. The corresponding aniline (2.2 equiv.) was added and the reaction was stirred at 65° C. for 16 h. The solvent was then removed under reduced pressure and purified by chromatography on SiO₂ with a solvent system of EtOAc/hexanes to yield the desired product, a 5-amino-6-alkoxy-[1,2,5]oxadiazolo[3,4-b]pyrazine. Scheme 3 illustrates general procedure 1-C.

General Procedure 1-D. Sodium hydride (1.2 equiv., 60% dispersion) was stirred in dry THF (0.2 M) under argon for 5 min. To the mixture, a solution of the appropriate amide in THF (0.2 M) was added dropwise over 1 min and the resulting mixture was allowed to stir at rt for 30 min. Then to the stirring mixture, a solution of 5-chloro-6-alkoxy-[1,2,5]oxadiazolo[3,4-b]pyrazine in dry THF (0.1 M 0.2 M) was added and the mixture was stirred at 70° C. for 16 h. The solvent was removed under reduced pressure and the residue was purified by chromatography on SiO₂ using a solvent system of EtOAc/hexanes to yield the desired product, a 5-amido-6-alkoxy-[1,2,5]oxadiazolo[3,4-b]pyrazine. Scheme 4 illustrates general procedure 1-D

General Procedures for the Preparation of Compounds 1 by Suzuki-Coupling

Prior to use, a mixture of water and 1,4-dioxane (1:2) was deoxygenated by sparging with N₂ for at least 10-30 min.

General Procedure 1-E. In a sealed vial, a mixture of aryl BPin (0.422 mmol), aryl halide (0.45 mmol), Pd(dppf)Cl₂.CH₂Cl₂ (0.024 mmol), and Na₂CO₃ (0.971 mmol) in deoxygenated dioxane/H₂O (2:1, 3 mL) was stirred at 90° C. under an atmosphere of N₂ overnight. The mixture was allowed to cool to room temperature, diluted with EtOAc, washed with 1 M HCl and brine, dried (Na₂SO₄), and concentrated to a brown residue. The residue was purified by chromatography on SiO₂ using a MeOH/CH₂Cl₂ solvent system to yield a solid. The solid was dissolved in a minimal amount of acetone and precipitated by the addition of hexanes. The precipitate was filtered, rinsed with hexanes, and collected to yield the desired product, a 6-biphenylamino-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-ol.

General Procedure 1-F. Halogenated (Br, I) aniline was installed onto 1-2 following general procedure 1-B. The resulting compound (0.616 mmol) was added to a reaction tube containing a stir bar followed by necessary aryl boronic acid (0.616 mmol), Na₂CO₃ (1.84 mmol), and Pd(dppf)Cl₂.CH₂Cl₂ (1 mol %). The tube was sealed, evacuated and filled with N2 (3×). Deoxygenated 1,4-dioxane:H₂O (2:1, 3 mL) was then added and the reaction was heated to 90° C. for 16 h. The reaction was allowed to cool to room temperature and the resulting biphasic mixture was condensed under reduced pressure and loaded onto Celite. Compound was purified by column chromatography on SiO₂ (gradient: 1-5% MeOH/CH₂Cl₂) to yield the desired product, a 6-biphenylamino-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-ol, as a solid. Scheme 5 illustrates Suzuki coupling general procedures 1-E (lower) and 1-F (upper).

General Procedure for the Preparation of Biphenyl Amine Intermediates

Prior to use, a mixture of water and dioxane was deoxygenated by sparging with N2 for at least 30 min.

General Procedure 1-G. In a sealed vial, a mixture of the aryl boronic acid or aryl BPin (1.3 equiv.), aryl halide (1.0 equiv.), Pd(dppf)Cl₂.CH₂Cl₂ (1-5 mol %), and Na₂CO₃ (2.3 equiv.) in deoxygenated dioxane/H₂O (2:1, 0.1-0.2 M) was stirred at 90° C. under an atmosphere of N2 overnight. The mixture was allowed to cool to room temperature, diluted with EtOAc, washed with brine, dried (Na₂SO₄), and concentrated to a residue. The residue was purified by chromatography on SiO₂ with a solvent system of EtOAc/hexanes to yield the desired aryl aniline Scheme 6 illustrates Suzuki coupling general procedure 1-G.

General Procedures for the Preparation of Alkynyl and Alkyl Aniline Intermediates

General Procedure 1-H. To a dry reaction tube containing a stir bar was added copper (I) iodide (0.038 mmol) PdCl₂(PPh₃)₂ (0.025 mmol), and halogenated aniline (1.27 mmol). The tube was sealed, evacuated, and refilled with N₂ (3×). Et₃N (3 mL) was then added followed by the necessary alkyne (2.53 mmol) and allowed to stir at room temperature for 48 h. The reaction mixture was filtered through Celite and rinsed with hexanes and concentrated. *Ethynyltrimethylsilane if present was removed by dissolving compound in EtOH (3 mL) and K₂CO₃ (1.56 mmol) was added. The mixture was heated to 50° C. and stirred for 1 h. The reaction was allowed to cool to room temperature and the solvent was removed under reduced pressure to yield desired alkyne substituted aniline.

General Procedure 1-I. The alkynyl aniline was added to a 2-neck round bottom with a stir bar affixed with septa followed by EtOH (3 mL), the resulting mixture was sparged with N2 for 10 min. 10% Pd/C was then added to the flask. The resulting mixture was placed under positive pressure of H2 gas (balloon) and allowed to stir overnight. The reaction was filtered over Celite, rinsing with EtOAc, and concentrated under reduced pressure to yield the alkane substituted aniline as a dark oil. Scheme 7 illustrates general procedures 1-H and 1-I.

General Procedures for the Preparation of Oxadiazolo Pyridine

General Procedure 1-J. 6 A sealed vial containing Pd₂dba₃ (10 mol percent), Xantphos (20 mol percent), 6-chloro-5-methoxy-[1,2,5]oxadiazolo[3,4-b]pyridine (1 equiv.) and K₂CO₃ (2.5 equiv.) was evacuated and backfilled with argon 3×. Deoxygenated anhydrous dioxane (0.2 M) was added through the septum, with the requisite aniline (1.1 equiv.). The mixture stirred at 110° C. for 16 h and then allowed to cool to room temperature. The mixture was filtered through Celite while being washed with ethyl acetate. The filtrate was collected, concentrated under reduced pressure, and purified via silica gel chromatography (Hexanes: Ethyl Acetate) to afford the desired product.

General Procedure 1-K. N-(2-fluorophenyl)-5-methoxy-[1,2,5]oxadiazolo[3,4-b]pyridin-6-amine (15 mg, 0.058 mmol) and Na₂CO₃ (18 mg, 0.17 mmol) were placed in a sealed vial and added Dioxane (0.5 mL) and water (0.5 mL). The mixture was stirred for 16 h at 110° C. and then allowed to room temperature. The mixture was acidified with 10% HCl aq. and precipitate was collected, washed with water, collected and dried to afford the desired product.

Hydroxy Series Compounds with Simple Halo Aniline

Example 3. Synthesis of 6-((2-Fluorophenyl)amino)-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-ol

6-((2-Fluorophenyl)amino)-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-ol (1-3) was synthesized by procedure 1-A to yield 1-3 in 8% as a pale yellow solid: ¹H NMR ((CD₃)₂CO, 500 MHz) δ 12.18 (br s, 1H), 9.23 (s, 1H), 8.51 (t, J=8.2 Hz, 1H), 7.35-7.27 (m, 3H); ¹⁹F NMR ((CD₃)₂CO, 376 MHz) δ 129.33 to −129.40 (m, 1 F); ¹³C NMR ((CD₃)₂CO, 126 MHz) δ 155.0 (d, J_(CF)=245.7 Hz), 153.5, 151.4, 150.2, 145.1, 127.2 (d, J_(CF)=7.7 Hz), 126.3 (d, J_(CF)=10.4 Hz), 125.6 (d, J_(CF)=3.9 Hz), 124.1, 116.2 (d, J_(CF)=19.5 Hz); HRMS (ESI⁻) m/z calc'd. for C₁₀H₅FN₅O₂ (M−H)⁻ 246.0433, found 246.0438.

Example 4. Synthesis of 6-((3-Fluorophenyl)amino)-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-ol

6-((3-Fluorophenyl)amino)-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-ol (1-4) was synthesized by procedure 1-A to yield 1-4 in 10% as a pale yellow solid: ¹H NMR ((CD₃)₂CO, 500 MHz) δ 12.09 (br s, 1H), 9.64 (s, 1H), 8.13 (dt, J=11.6, 2.4 Hz, 1H), 7.90 (dd, J=8.2, 2.0 Hz, 1H), 7.48 (q, J=8.0 Hz, 1H), 6.99 (dt, J=8.4, 2.5 Hz, 1H); ¹⁹F NMR ((CD₃)₂CO, 376 MHz) δ−113.15 to −113.22 (m, 1 F); ¹³C NMR ((CD₃)₂CO, 126 MHz) δ 163.6 (d, J_(CF)=242.4 Hz), 153.4, 151.4, 150.2, 145.1, 140.4 (d, J_(CF)=11.1 Hz), 131.3 (d, J_(CF)=9.4 Hz), 117.9 (d, J_(CF)=3.1 Hz), 112.3 (d, J_(CF)=21.3 Hz), 109.0 (d, J_(CF)=26.9 Hz); HRMS (ESI⁻) m/z calc'd. for C₁₀H₅FN₅O₂ (M−H)⁻246.0433, found 246.0440.

Example 5. Synthesis of 6-((4-Fluorophenyl)amino)-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-ol

6-((4-Fluorophenyl)amino)-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-ol (1-5) was synthesized by procedure 1-B to yield 1-5 in 44% as a yellow solid: ¹H NMR (400 MHz, Acetone-d₆) δ11.69 (s, 1H), 9.58 (s, 1H), 8.19-8.11 (m, 2H), 7.28-7.19 (m, 2H); ¹⁹F NMR (376 MHz, Acetone-d₆) δ−118.44-118.56 (m, 1F); ¹³C NMR (101 MHz, Acetone-d₆) δ 160.59 (d, J_(CF)=243.0 Hz), 153.61, 151.22, 150.43, 145.15, 135.03 (d, J_(CF)=2.7 Hz), 124.25, 124.17, 116.41, 116.18; HRMS (ESI⁺) m/z calc'd for C₁₀H₇FN₅O₂ (M+H)⁺248.0578, found 248.0591.

Example 6. Synthesis of 6-((2-(Trifluoromethyl)phenyl)amino)-[1,2,5]oxadiazolo[3,4-B]pyrazin-5-ol

6-((2-(Trifluoromethyl)phenyl)amino)-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-ol (1-6) was synthesized by procedure 1-B to yield 1-6 in 5% as a yellow solid: ¹H NMR (400 MHz, Acetone-d₆) δ 9.38 (s, 1H), 8.62-8.52 (m, 1H), 7.87-7.79 (m, 3H), 7.50 (tp, J=7.7, 1.0 Hz, 1H); ¹⁹F NMR (376 MHz, Acetone-d₆) δ Rotamers −61.19, −61.21; HRMS (ESI⁺) m/z calc'd for C₁₁H₇F₃N₅O₂ (M+H)⁺298.0546, found 298.0538.

Example 7. Synthesis of 6-((4-(Trifluoromethyl)phenyl)amino)-[1,2,5]oxadiazolo[3,4-B]pyrazin-5-ol (1-7)

6-((4-(Trifluoromethyl)phenyl)amino)-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-ol (1-7) was synthesized by procedure 1-A to yield 1-7 in 66% as a yellow solid: ¹H NMR ((CD₃)₂CO, 500 MHz) δ 12.11 (br s, 1H), 9.77 (s, 1H), 8.37 (d, J=8.3 Hz, 2H), 7.80 (d, J=8.3 Hz, 2H); ¹⁹F NMR ((CD₃)₂CO, 376 MHz) δ-62.59 (s, 3 F); ¹³C NMR ((CD₃)₂CO, 126 MHz) δ 153.4, 151.6, 150.2, 145.1, 142.1, 127.0 (q, J_(CF)=3.8 Hz), 126.7 (q, J_(CF)=32.6 Hz), 125.3 (q, J_(CF)=270.8 Hz), 122.2; HRMS (ESI⁻) m/z calc'd. for C₁₁H₅F₃N₅O₂ (M−H)⁻296.0401, found 296.0419.

Example 8. Synthesis of 6-((2-(Trifluoromethoxy)phenyl)amino)-[1,2,5]oxadiazolo[3,4-B]pyrazin-5-ol

6-((2-(Trifluoromethoxy)phenyl)amino)-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-ol (1-8) was synthesized by procedure 1-A to yield 1-8 in 27% as a yellow solid: ¹H NMR ((CD₃)₂CO, 500 MHz) δ 12.25 (br s, 1H), 9.34 (s, 1H), 8.75 (d, J=8.1, 1H), 7.57-7.50 (m, 2H), 7.38 (t, J=7.5 Hz, 1H); ¹⁹F NMR ((CD₃)₂CO, 376 MHz) δ rotamers −58.516 (s), −58.522 (s); ¹³C NMR ((CD₃)₂CO, 126 MHz) δ 153.7, 151.3, 150.2, 145.2, 140.5 (q, J_(CF)=1.2 Hz), 130.8, 128.9, 126.8, 123.7, 121.9, 121.6 (q, J_(CF)=258.0 Hz); HRMS (ES⁺) m/z calc'd. for C₁₁H₇F₃N₅O₃ (M+H)⁺314.0496, found 314.0474.

Example 9. Synthesis of 6-((3-(Trifluoromethoxy)phenyl)amino)-[1,2,5]oxadiazolo[3,4-B]pyrazin-5-ol

6-((3-(Trifluoromethoxy)phenyl)amino)-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-ol (1-9) was synthesized by procedure 1-A to yield 1-9 in 64% as a yellow solid: ¹H NMR ((CD₃)₂CO, 500 MHz) δ 12.01 (br s, 1H), 9.73 (s, 1H), 8.29 (s, 1H), 8.13 (d, J=8.0 Hz, 1H), 7.58 (t, J=8.3 Hz, 1H), 7.18 (d, J=8.3 Hz, 1H); ¹⁹F NMR ((CD₃)₂CO, 376 MHz) δ-58.5 (s, 3F); ¹³C NMR ((CD₃)₂CO, 126 MHz) δ 153.4, 151.5, 150.2, 150.1 (q, J_(CF)=3.8 Hz), 145.1, 140.3, 131.3, 121.5 (q, J_(CF)=255.9 Hz), 120.7, 117.8, 114.6; HRMS (ESI⁻) m/z calc'd. for C₁₁H₅F₃N₅O₃ (M−H)⁻312.0350, found 312.0372.

Example 10. Synthesis of 6-((4-(Trifluoromethoxy)phenyl)amino)-[1,2,5]oxadiazolo[3,4-B]pyrazin-5-ol

6-((4-(Trifluoromethoxy)phenyl)amino)-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-ol (1-10) was synthesized by procedure 1-A to yield 1-10 in 75% as a yellow solid: ¹H NMR ((CD₃)₂CO, 500 MHz) δ 12.07 (br s, 1H), 9.67 (s, 1H), 8.27-8.24 (m, 2H), 7.43 (d, J=9.1 Hz, 2H); ¹⁹F NMR ((CD₃)₂CO, 376 MHz) δ-58.79 (s, 3F); ¹³C NMR ((CD₃)₂CO, 126 MHz) δ 153.5, 151.3, 150.3, 146.4 (q, J_(CF)=2.0 Hz), 145.1, 137.7, 123.7, 122.5, 121.5 (q, J_(CF)=255.3 Hz); HRMS (ESI⁻) m/z calc'd for C₁₁H₅F₃N₅O₃ (M−H)⁻ 312.0350, found 312.0369.

Example 11. Synthesis of 6-((3-Fluoro-4-(trifluoromethoxy)phenyl)amino)-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-ol

6-((3-Fluoro-4-(trifluoromethoxy)phenyl)amino)-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-ol (1-11) was synthesized by procedure 1-A to yield 1-11 in 51% as a yellow solid: ¹H NMR ((CD₃)₂CO, 400 MHz) δ 12.10 (br s, 1H), 9.82 (br s, 1H), 8.40-8.36 (m, 1H), 8.08-8.04 (m, 1H), 7.62-7.58 (m, 1H); ¹⁹F NMR ((CD₃)₂CO, 376 MHz) δ−59.87-−59.88 (m, 3F), −128.86-−128.96 (m, 1F); ¹³C NMR ((CD₃)₂CO, 126 MHz) δ 154.9 (d, J_(CF)=248.7 Hz), 153.3, 151.5, 150.1, 145.1, 139.2 (d, J_(CF)=10.0 Hz), 133.1 (d, J_(CF)=12.5 Hz), 125.2, 121.5 (q, J_(CF)=257.2 Hz), 118.6 (d, J_(CF)=3.7 Hz), 110.9 (d, J_(CF)=24.4 Hz); HRMS (ESI⁻) m/z calc'd for C₁₁H₄F₄N₅O₃ (M−H)⁻330.0256, found 330.0289.

Example 12. Synthesis of 6-((2-Methyl-5-(trifluoromethyl)phenyl)amino)-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-ol

6-((2-Methyl-5-(trifluoromethyl)phenyl)amino)-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-ol (1-12) was synthesized by procedure 1-B to yield 1-12 in 17% as a yellow solid: ¹H NMR (400 MHz, Acetone-d₆) δ 11.98 (s, 1H), 9.34 (s, 1H), 8.46-8.36 (m, 1H), 7.62-7.50 (m, 2H), 2.49 (s, 3H); ¹⁹F NMR (376 MHz, Acetone-d₆) δ−62.87 (s, 3F); ¹³C NMR (101 MHz, Acetone-d₆) δ 152.75, 151.27, 149.46, 144.34, 136.38, 136.26, 131.46, 128.27 (q, J=32.4 Hz), 124.30 (q, J=271.2 Hz), 122.51 (q, J=3.9 Hz), 120.68 (q, J=4.1 Hz), 17.02 HRMS (ESI⁺) m/z calc'd. for C₁₂H₉F₃N₅O₂ (M+H)⁺312.0702, found 312.0700.

Example 13. Synthesis of 6-((2,6-Difluorophenyl)amino)-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-ol

6-((2,6-Difluorophenyl)amino)-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-ol (1-13) was synthesized by procedure 1-B to yield 1-13 in 23% as a yellow solid: ¹H NMR (400 MHz, Acetone-d₆) δ 11.67 (s, 1H), 9.41 (s, 1H), 7.54-7.45 (m, 1H), 7.22-7.15 (m, 2H); ¹⁹F NMR (376 MHz, Acetone-d₆) δ −117.87-−117.95 (m, 2F); ¹³C NMR (101 MHz, Acetone-d₆) δ 159.39 (dd, J_(CF)=250.9, 4.7 Hz), 153.24, 152.95, 150.32, 145.43, 130.18 (t, J_(CF)=9.9 Hz), 114.67 (t, J_(CF)=16.6 Hz), 112.70 (dd, J_(CF)=16.8, 3.4 Hz), 112.70 (d, J_(CF)=23.8 Hz); HRMS (ESI⁺) m/z calc'd. for C₁₀H₆F₂N₅O₂ (M+H)⁺266.0484, found 266.0480.

Example 14. Synthesis of 6-((2,3-Difluorophenyl)amino)-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-ol

6-((2,3-Difluorophenyl)amino)-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-ol (1-14) was synthesized by procedure 1-B to yield 1-14 in 29% as a yellow solid: ¹H NMR (400 MHz, Acetone-d₆) δ 11.09 (s, 1H), 9.35 (s, 1H), 8.24-8.17 (m, 1H), 7.38-7.30 (m, 1H), 7.29-7.20 (m, 1H); ¹⁹F NMR (376 MHz, Acetone-d₆) δ−139.53-−139.84 (m, 1F), −152.07-−152.34 (m, 1F); ¹³C NMR (101 MHz, Acetone-d₆) δ 153.44, 151.82, 151.32 (dd, J_(CF)=245.6, 11.0 Hz), 150.19, 145.29, 143.95 (dd, J_(CF)=247.2, 14.6 Hz), 128.17 (dd, J_(CF)=7.8, 1.9 Hz), 125.42 (dd, J_(CF)=8.0, 5.0 Hz), 120.10 (d, J_(CF)=3.5 Hz), 114.70 (d, J_(CF)=16.9 Hz)HRMS (ESI⁺) m/z calc'd. for C₁₀H₆F₂N₅O₂ (M+H)⁺266.0484, found 266.0479.

Example 15. 6-((3,5-Difluorophenyl)amino)-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-ol

6-((3,5-Difluorophenyl)amino)-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-ol (1-15) was synthesized by procedure 1-B to yield 1-15 in 19% as a yellow solid. ¹H NMR (400 MHz, Acetone-d₆) δ 12.11 (s, 1H), 9.76 (s, 1H), 7.97-7.88 (m, 2H), 6.87 (tt, J=9.1, 2.3 Hz, 1H); ¹⁹F NMR (376 MHz, Acetone-d₆) δ−110.23-−110.33 (m, 2F). ¹³C NMR (101 MHz, Acetone-d₆) δ163.84 (dd, J_(CF)=244.1, 14.8 Hz), 153.20, 151.51, 149.93, 145.01, 141.14 (t, J_(CF)=13.9 Hz), 104.97 (dd, J_(CF)=21.1, 9.1 Hz), 100.56 (t, J_(CF)=26.2 Hz); HRMS (ESI⁺) m/z calc'd for C₁₀H₆F₂N₅O₂ (M+H)⁺266.0484, found 266.0488.

Example 16. Synthesis of 6-((2-Fluoro-4-(trifluoromethyl)phenyl)amino)-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-ol

6-((2-Fluoro-4-(trifluoromethyl)phenyl)amino)-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-ol was synthesized by procedure 1-B to yield 1-16 in 14% as a yellow solid:¹H NMR (500 MHz, Acetone-d₆) δ 11.92 (s, 1H), 9.37 (s, 1H), 8.81 (t, J=8.3 Hz, 1H), 7.79-7.67 (m, 2H); ¹⁹F NMR (376 MHz, Acetone-d₆) δ−62.82 (s, 3F), −127.05 (t, J=10.5 Hz, 1F); ¹³C NMR (126 MHz, Acetone-d₆) δ 154.24 (d, J_(CF)=248.5 Hz), 153.42, 151.57, 149.99, 145.25, 130.13 (d, J_(CF)=11.3 Hz), 127.73 (dd, J_(CF)=35.9, 7.6 Hz), 124.44 (dq, J_(CF)=271.1, 3.1 Hz), 124.09, 122.97 (p, J_(CF)=4.3 Hz), 113.69 (dq, J_(CF)=23.1, 4.2 Hz); HRMS (ESI⁺) m/z calc'd for C₁₁H₆F₄N₅O₂ (M+H)⁺316.0452, found 316.0453.

Example 17. Synthesis of 6-((2-Fluoro-5-(trifluoromethyl)phenyl)amino)-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-ol

6-((2-Fluoro-5-(trifluoromethyl)phenyl)amino)-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-ol was synthesized by procedure 1-B to yield 1-17 in 26% as a yellow solid: ¹H NMR (400 MHz, Acetone-d₆) δ 11.99 (s, 1H), 9.40 (s, 1H), 8.90 (dd, J=7.4, 1.9 Hz, 1H), 7.72-7.66 (m, 1H), 7.63-7.56 (m, 1H); ¹⁹F NMR (376 MHz, Acetone-d₆) δ-62.66 (s, 3F), −122.44-−122.53 (m, 1F); ¹³C NMR (126 MHz, Acetone-d₆) δ 157.04 (d, J_(CF)=252.7 Hz), 153.54, 151.91, 150.11, 145.44, 127.63 (d, J_(CF)=4.0 Hz), 127.44 (d, J_(CF)=11.6 Hz), 124.86 (q, J_(CF)=271.4 Hz), 124.49 (dd, J_(CF)=9.5, 4.3 Hz), 121.50-121.41 (m), 117.50 (d, J_(CF)=21.2 Hz); HRMS (ESI⁺) m/z calc'd for C₁₁H₆F₄N₅O₂ (M+H)⁺316.0452, found 316.0476.

Example 18. Synthesis of 6-((3-Iodophenyl)amino)-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-ol

6-((3-Iodophenyl)amino)-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-ol was synthesized by procedure 1-B to yield 1-18 in 47% as a yellow solid: ¹H NMR (400 MHz, Acetone-d₆) δ12.06 (s, 1H), 9.56 (s, 1H), 8.62 (t, J=1.9 Hz, 1H), 8.14 (ddd, J=8.3, 2.1, 0.9 Hz, 1H), 7.60 (ddd, J=7.9, 1.7, 0.9 Hz, 1H), 7.25 (t, J=8.1 Hz, 1H); ¹³C NMR (126 MHz, Acetone-d₆) δ153.47, 151.34, 150.26, 145.15, 140.02, 134.72, 131.56, 130.61, 121.53, 94.30; HRMS (ESI⁺) m/z calc'd for C₁₀H₇IN₅O₂ (M+H)⁺355.9638, found 355.9648.

Example 19. Synthesis of 6-((4-Iodophenyl)amino)-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-ol

6-((4-Iodophenyl)amino)-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-ol (1-19) was synthesized by procedure 1-B to yield 1-19 in 61% as a yellow solid. ¹H NMR (400 MHz, Acetone-d₆) δ11.89 (s, 1H), 9.59 (s, 1H), 8.01-7.96 (m, 2H), 7.84-7.79 (m, 2H); HRMS (ESI⁺) m/z calc'd. for C₁₀H₇IN₅O₂ (M+H)+355.9638, found 355.9641.

Example 20. Synthesis of 6-((2-Chlorophenyl)amino)-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-ol

6-((2-Chlorophenyl)amino)-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-ol (1-20) was synthesized by procedure 1-A to yield 1-20 in 24% as a yellow solid: ¹H NMR ((CD₃)₂CO, 400 MHz) δ12.26 (br s, 1H), 9.51 (br s, 1H), 8.78-8.75 (m, 1H), 7.62-7.59 (m, 1H), 7.54-7.50 (m, 1H), 7.30-7.26 (m, 1H); ¹³C NMR ((CD₃)₂CO, 126 MHz) δ 153.7, 151.2, 150.2, 145.1, 134.8, 130.4, 129.0, 127.0, 126.9*, 125.3, 123.1, 123.0*; HRMS (ESI⁻) m/z calc'd for C₁₀H₅ClN₅O₂ (M−H)⁻262.0137, found 262.0160.

Example 21. Synthesis of 6-((2-Chlorophenyl)amino)-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-ol

6-((4-Chlorophenyl)amino)-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-ol (1-21) was synthesized by procedure 1-A to yield 1-21 in 59% as a yellow solid: ¹H NMR ((CD₃)₂CO, 500 MHz) δ12.06 (br s, 1H), 9.61 (br s, 1H), 8.18-8.15 (m, 2H), 7.50-7.47 (m, 2H); ¹³C NMR ((CD₃)₂CO, 126 MHz) M53.5, 151.3, 150.3, 145.1, 137.6, 130.4, 129.7, 123.7; HRMS (ES⁺) m/z calc'd for C₁₀H₇ClN₅O₂ (M+H)⁺264.0283, found 264.0289.

Example 22. Synthesis of 6-((2-Methoxy-4-(trifluoromethoxy)phenyl)amino)-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-ol

6-((2-Methoxy-4-(trifluoromethoxy)phenyl)amino)-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-ol (1-22) was synthesized by procedure 1-A to yield 1-22 in 68% as an orange solid: ¹H NMR ((CD₃)₂CO, 500 MHz) δ 12.20 (br s, 1H), 9.46 (s, 1H), 8.86 (d, J=8.9 Hz, 1H), 7.15 (d, J=2.6 Hz, 1H), 7.09 (dt, J=9.0, 2.6 Hz, 1H), 4.10 (s, 3H); ¹⁹F NMR ((CD₃)₂CO, 376 MHz) δ−58.70 (s, 3 F); ¹³C NMR ((CD₃)₂CO, 126 MHz) δ 153.8, 151.1, 150.6, 150.3, 146.5 (q, J_(CF)=2.1 Hz), 145.1, 126.7, 121.5 (q, J_(CF)=255.6 Hz), 121.3, 113.7, 105.7, 57.3; HRMS (ESI⁻) m/z calc'd for C₁₂H₇F₃N₅O₄ (M−H)⁻342.0456, found 342.0448.

Example 23. Synthesis of 6-((2-Fluorophenyl)(methyl)amino)-[1,2,5]oxadiazolo[3,4-B]pyrazin-5-ol

6-((2-Fluorophenyl)(methyl)amino)-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-ol (1-23) synthesized by procedure 1-A to yield 1-23 in 42% as a yellow solid: ¹H NMR ((CD₃)₂CO, 500 MHz) δ 11.63 (br s, 1H), 7.47-7.42 (m, 1H), 7.40-7.34 (m, 1H), 7.26-7.20 (m, 2H), 3.54 (s, 3H); ¹⁹F NMR ((CD₃)₂CO, 376 MHz) δ-125.48-−125.68 (m, 1 F); ¹³C NMR ((CD₃)₂CO, 126 MHz) δ158.0 (d, J_(CF)=245.9 Hz), 154.6, 152.3, 150.4, 145.7, 134.6 (d, J_(CF)=12.8 Hz), 129.7 (d, J_(CF)=7.8 Hz), 128.7, 125.6 (d, J_(CF)=3.9 Hz), 116.7 (d, J_(CF)=20.2 Hz), 42.6; HRMS (ESI⁻) m/z calc'd. for C₁₁H₇FN₅O₂ (M−H)⁻260.0589, found 260.0593.

Example 24. Synthesis of 6-((3-Chloro-4-(trifluoromethoxy)phenyl)amino)-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-ol

6-((3-Chloro-4-(trifluoromethoxy)phenyl)amino)-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-ol (1-24) was synthesized by procedure 1-A to yield 1-24 in 51% as a yellow-orange solid: ¹H NMR ((CD₃)₂CO, 500 MHz) δ 12.05 (br s, 1H), 9.78 (s, 1H), 8.53 (d, J=2.7 Hz, 1H), 8.21 (dd, J=9.1, 2.6 Hz, 1H), 7.60 (dq, J=9.0, 1.4 Hz, 1H); ¹⁹F NMR ((CD₃)₂CO, 376 MHz) δ−58.87-−58.88 (m, 3 F); ¹³C NMR ((CD₃)₂CO, 126 MHz) δ 153.34, 151.53, 150.06, 145.16, 141.98 (q, J=2.0 Hz), 138.77, 127.82, 124.29, 123.85, 122.07, 121.48 (q J=257.3 Hz); HRMS (ESI⁻) m/z calc'd for C₁₁H₄ClF₃N₅O₃ (M−H)⁻ 345.9960, found 345.9949.

Example 25. Synthesis of 6-((4-((Trifluoromethyl)thio)phenyl)amino)-[1,2,5]oxadiazolo[3,4-B]pyrazin-5-ol

6-((4-((Trifluoromethyl)thio)phenyl)amino)-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-ol (1-25). was synthesized by procedure 1-A to yield 1-25 in 23% as a pale yellow solid: ¹H NMR ((CD₃)₂CO, 500 MHz) δ 12.11 (br s, 1H), 9.74 (s, 1H), 8.33-8.31 (m, 2H), 7.82-7.80 (m, 2H); ¹⁹F NMR ((CD₃)₂CO, 376 MHz) δ-44.23 (s, 3F); ¹³C NMR ((CD₃)₂CO, 126 MHz) δ153.4, 151.5, 150.2, 145.1, 141.6, 138.1, 130.8 (q, J_(CF)=307.1 Hz), 123.0, 119.7 (q, J_(CF)=2.2 Hz); HRMS (ESI⁻) m/z calc'd for C₁₁H₅F₃N₅O₂S (M−H)⁻328.0122, found 328.0113.

Example 26. Synthesis of 6-((4-(1,1,1,3,3,3-Hexafluoro-2-hydroxypropan-2-yl)phenyl)amino)-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-ol

6-((4-(1,1,1,3,3,3-Hexafluoro-2-hydroxypropan-2-yl)phenyl)amino)-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-ol (1-26) was prepared as follows. In a screw-cap vial, a mixture of 1-2 (0.200 g, 1.05 mmol), 2-(4-aminophenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol (0.125 g, 0.482 mmol), and NaHCO₃ (0.100 g, 1.19 mmol) in acetone/H₂O (9:1, 4 mL) was stirred at room temperature for 18 h. The mixture was diluted with an aqueous solution of KOH (0.320 g in 4 mL) and stirring was continued for 2 h. The mixture was acidified with 1 M HCl and extracted with EtOAc. The organic layer was washed with brine, dried (Na₂SO₄), and concentrated to an orange residue. The residue was purified by chromatography on SiO₂ (gradient: 0-3% MeOH/CH₂C₁₂) to yield a sticky yellow solid (0.196 g). The solid was dissolved in a minimal amount of acetone and then precipitated by the addition of hexanes. The precipitate was filtered, rinsed with hexanes, and collected to yield 1-26 (0.155 g, 81%) as an off-white solid: ¹H NMR ((CD₃)₂CO, 500 MHz) δ 12.08 (br s, 1H), 9.69 (s, 1H), 8.30-8.28 (m, 2H), 7.87 (d, J=8.7 Hz, 2H), 7.52 (br s, 1H); ¹⁹F NMR ((CD₃)₂CO, 376 MHz) δ-75.64 (s, 6F); ¹³C NMR ((CD₃)₂CO, 125 MHz) δ 153.5, 151.5, 150.3, 145.1, 140.4, 128.5, 127.7, 124.1 (q, J_(CF)=288.1 Hz), 122.0, 78.1 (p, J_(CF)=29.7 Hz); HRMS (ES⁺) m/z calc'd for C₁₃H₈F₆N₅O₃ (M+H)⁺396.0526, found 396.0530.

Example 27. Synthesis of 6-((4-(Difluoromethoxy)phenyl)amino)-[1,2,5]oxadiazolo[3,4-B]pyrazin-5-ol

6-((4-(Difluoromethoxy)phenyl)amino)-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-ol (1-27) was synthesized by procedure 1-A to yield 1-27 in 72% as a pale yellow solid: ¹H NMR ((CD₃)₂CO, 500 MHz) δ 12.05 (br s, 1H), 9.60 (s, 1H), 8.19-8.15 (m, 2H), 7.31-7.27 (m, 2H), 7.01 (t, J_(HF)=74.3 Hz, 1H); ¹⁹F NMR ((CD₃)₂CO, 376 MHz) δ−82.64 (d, J=74.1 Hz, 2F); ¹³C NMR ((CD₃)₂CO, 126 MHz) δ 153.5, 151.2, 150.4, 149.1 (t, J_(CF)=3.2 Hz), 145.1, 136.0, 123.8, 120.5, 117.5 (t, J_(CF)=257.4 Hz); HRMS (ES⁺) m/z calc'd for C₁₁H₈F₂N₅O₃ (M+H)⁺296.0590, found 296.0594.

Example 28. Synthesis of 6-((4-(1,1,2,2-Tetrafluoroethoxy)phenyl)amino)-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-ol

6-((4-(1,1,2,2-Tetrafluoroethoxy)phenyl)amino)-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-ol (1-28) was synthesized by procedure 1-A to yield 1-28 in 70% as a yellow solid:¹H NMR ((CD₃)₂CO, 500 MHz) δ 12.07 (br s, 1H), 9.66 (s, 1H), 8.25-8.21 (m, 2H), 7.40-7.38 (m, 2H), 6.53 (tt, J_(HF)=52.5, 3.0 Hz, 1H); ¹⁹F NMR ((CD₃)₂CO, 376 MHz) δ−89.10 (td, J=5.5, 2.7 Hz, 2F), −138.63 (dt, J=52.4, 5.8 Hz, 2F); ¹³C NMR ((CD₃)₂CO, 126 MHz) δ 153.5, 151.3, 150.3, 146.1 (t, J_(CF)=2.1 Hz), 145.1, 137.3, 123.6, 123.1, 117.6 (tt, J_(CF)=270.0, 28.6 Hz), 109.07 (tt, J_(CF)=249.0, 40.7 Hz); HRMS (ES⁺) m/z calc'd. for C₁₂H₈F₄N₅O₃ (M+H)⁺346.0558, found 346.0562.

Example 29. Synthesis of 6-((4-(Chlorodifluoromethoxy)phenyl)amino)-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-ol

6-((4-(Chlorodifluoromethoxy)phenyl)amino)-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-ol (1-29) was synthesized by procedure 1-A to yield 1-29 in 65% as a pale yellow solid: ¹H NMR ((CD₃)₂CO, 500 MHz) δ12.08 (br s, 1H), 9.69 (s, 1H), 8.29-8.25 (m, 2H), 7.46-7.43 (m, 2H); ¹⁹F NMR ((CD₃)₂CO, 376 MHz) δ-26.23 (s, 2F); ¹³C NMR ((CD₃)₂CO, 126 MHz) δ153.5, 151.4, 150.3, 147.5, 145.1, 137.9, 126.3 (t, J_(CF)=286.8 Hz), 123.6, 122.9; HRMS (ES⁺) m/z calc'd. for C₁₁H₇ClF₂N₅O₃ (M+H)⁺330.0200, found 330.0202.

Example 30. Synthesis of 6-((4-(Pentafluoro-l6-sulfaneyl)phenyl)amino)-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-ol

6-((4-(Pentafluoro-16-sulfaneyl)phenyl)amino)-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-ol (1-30) was synthesized by procedure 1-A to yield 1-30 in 38% as a colorless cloth-like solid: ¹H NMR ((CD₃)₂CO, 500 MHz) δ 12.10 (br s, 1H), 9.83 (s, 1H), 8.38 (d, J=8.9 Hz, 2H), 7.99-7.96 (m, 2H); ¹⁹F NMR ((CD₃)₂CO, 376 MHz) δ−120.74-−121.67 (m, 5F); ¹³C NMR ((CD₃)₂CO, 126 MHz) δ 153.4, 151.6, 150.1, 150.1 (p, J_(CF)=17.5 Hz), 145.2, 141.8, 127.8 (p, J_(CF)=4.8 Hz), 121.9; HRMS (ESI) m/z calc'd. for C₁₀H₅F₅N₅O₂S (M−H)⁻354.0090, found 354.0080.

Example 31. Synthesis of 6-((4-(Pentafluoro-l6-sulfaneyl)phenyl)amino)-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-ol

6-((3-(Pentafluoro-16-sulfaneyl)phenyl)amino)-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-ol (1-31) was synthesized by procedure 1-A to yield 1-31 in 37% as a colorless solid: ¹H NMR ((CD₃)₂CO, 400 MHz) δ 12.05 (br s, 1H), 9.88 (s, 1H), 8.77-8.76 (m, 1H), 8.46-8.42 (m, 1H), 7.74-7.69 (m, 2H); ¹⁹F NMR ((CD₃)₂CO, 376 MHz) δ−120.78-−121.70 (m, SF); ¹³C NMR ((CD₃)₂CO, 126 MHz) δ 154.6 (p, J_(CF)=17.1 Hz), 153.4, 151.7, 150.1, 145.2, 139.4, 130.5, 125.6, 122.9 (p, J_(CF)=4.3 Hz), 119.7 (p, J_(CF)=4.9 Hz); HRMS (ESI⁺) m/z calc'd. for C₁₀H₇F₅N₅O₂S (M+H)⁺356.0235, found 356.0232.

Example 32. Synthesis of 6-((2-Methyl-4-(trifluoromethoxy)phenyl)amino)-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-ol

6-((2-Methyl-4-(trifluoromethoxy)phenyl)amino)-[1,2,5]oxadiazolo[3,4-b]pyrazin-S-ol (1-32) was synthesized by procedure 1-A to yield 1-32 in 42% as a pale yellow crystalline solid: ¹H NMR ((CD₃)₂CO, 500 MHz) δ 12.08 (br s, 1H), 9.23 (s, 1H), 8.09 (d, J=8.8 Hz, 1H), 7.32 (d, J=2.8 Hz, 1H), 7.29 (dd, J=8.7, 2.8 Hz, 1H), 2.44 (s, 3H); ¹⁹F NMR ((CD₃)₂CO, 376 MHz) δ-58.62 (s, 3F); ¹³C NMR ((CD₃)₂CO, 126 MHz) δ 153.7, 152.1, 150.5, 147.4 (q, J_(CF)=1.7 Hz), 145.2, 135.5, 135.4, 126.7, 123.9, 121.5 (q, J_(CF)=255.5 Hz), 119.8, 17.9; HRMS (ESI⁺) m/z calc'd. for C₁₂H₉F₃N₅O₃ (M+H)⁺328.0652, found 328.0650.

Example 33. Synthesis of 6-((3-Bromo-4-fluorophenyl)amino)-[1,2,5]oxadiazolo[3,4-B]pyrazin-S-ol

6-((3-Bromo-4-fluorophenyl)amino)-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-ol (1-33) was synthesized by procedure 1-B to yield 1-33 in 10% as a yellow solid: ¹H NMR (400 MHz, Acetone-d₆) δ 11.79 (s, 1H), 9.68 (s, 1H), 8.56 (dd, J=6.2, 2.7 Hz, 1H), 8.14 (ddd, J=9.0, 4.3, 2.7 Hz, 1H), 7.39 (dd, J=9.0, 8.4 Hz, 1H); HRMS (ESI⁻) m/z calc'd. for C₁₀H₄BrFN₅O₂ (M−H)⁻323.9527, found 323.9533.

Example 34. Synthesis of 6-((3,5-Bis(trifluoromethyl)phenyl)amino)-[1,2,5]oxadiazolo[3,4-B]pyrazin-5-ol

6-((3,5-Bis(trifluoromethyl)phenyl)amino)-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-ol (1-34) was synthesized by procedure 1-B to yield 1-34 in 6% as a yellow solid: ¹H NMR (400 MHz, Acetone-d₆) δ 11.81 (s, 1H), 10.08 (s, 1H), 8.93-8.86 (m, 2H), 7.89-7.85 (m, 1H); HRMS (ESI⁻) m/z Calc'd. for C₁₀H₄BrFN₅O₂ (M−H)⁻364.0274, found 364.0261.

Example 35. Synthesis of 6-((4-IODO-2-(trifluoromethoxy)phenyl)amino)-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-ol

6-((4-Iodo-2-(trifluoromethoxy)phenyl)amino)-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-ol (1-35) was synthesized by procedure 1-B to yield 1-35 in 8% as a yellow solid: ¹H NMR (400 MHz, Acetone-d₆) δ 11.68 (s, 1H), 9.32 (s, 1H), 8.56 (d, J=8.7 Hz, 1H), 7.94 (ddd, J=8.7, 1.9, 0.5 Hz, 1H), 7.87 (p, J=1.6 Hz, 1H); ¹⁹F NMR (376 MHz, Acetone-d₆) δ-58.63 (s, 3F); ¹³C NMR (101 MHz, Acetone-d₆) δ 153.70, 151.35, 150.10, 145.32, 140.54 (q, J_(CF)=1.9 Hz), 138.25, 131.08, 130.77 (q, J_(CF)=1.7 Hz), 125.12, 121.49 (q, J_(CF)=259.0 Hz), 88.00; HRMS (ESI⁻) m/z calc'd. for C₁₁H₄F₃IN₅O₃ (M−H)⁻ 437.9316, found 437.9300.

Example 36. Synthesis of 6-((2-Fluoro-4-(trifluoromethoxy)phenyl)amino)-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-ol

6-((2-Fluoro-4-(trifluoromethoxy)phenyl)amino)-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-ol (1-36) was synthesized by procedure 1-B to yield 1-36 in 23% as a yellow solid: ¹H NMR (400 MHz, Acetone-d₆) δ 11.53 (s, 1H), 9.30 (s, 1H), 8.56 (t, J=8.9 Hz, 1H), 7.61-7.28 (m, 2H); ¹⁹F NMR (376 MHz, Acetone-d₆) δ-59.02 (s, 3F), −123.51-−123.59 (m, 1F); ¹³C NMR (101 MHz, Acetone-d₆) δ155.07 (d, J_(CF)=249.9 Hz), 153.43, 151.69, 150.14, 146.62 (dd, J_(CF)=10.7, 2.3 Hz), 145.26, 125.70 (d, J_(CF)=10.7 Hz), 125.48 (d, J_(CF)=2.3 Hz), 121.33 (q, J_(CF)=256.6 Hz), 118.29 (dd, J_(CF)=4.2, 1.2 Hz), 110.42 (dd, J_(CF)=23.6, 1.3 Hz); HRMS (ESI⁻) m/z calc'd. for C₁₁H₄F₄N₅O₃ (M−H)⁻330.0255, found 330.0257.

Example 37. Synthesis of 6-((2-Fluoro-3-(trifluoromethyl)phenyl)amino)-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-ol

6-((2-Fluoro-3-(trifluoromethyl)phenyl)amino)-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-ol (1-37) was synthesized by procedure 1-B to yield 1-37 in 21% as a yellow solid: ¹H NMR (400 MHz, Acetone-d₆) δ 12.21 (s, 1H), 9.41 (s, 1H), 8.75-8.65 (m, 1H), 7.69-7.51 (m, 2H); ¹⁹F NMR (376 MHz, Acetone-d₆) δ−61.75 (d, J=13.0 Hz, 3F), −129.74-−129.93 (m, 1F); ¹³C NMR (101 MHz, Acetone-d₆) δ rotamers 152.43, 152.39*, 151.54 (dd, J_(CF)=256.3, 2.4 Hz), 151.00, 150.88*, 149.17, 149.16*, 144.35, 128.18 (d, J_(CF)=18.9 Hz), 126.82, 125.37 (d, J_(CF)=271.6 Hz), 124.96 (dd, J_(CF)=5.1, 2.1 Hz), 123.04 (dd, J_(CF)=4.7, 1.2 Hz), 117.93 (dd, J_(CF)=33.1, 10.8 Hz); HRMS (ESI⁻) m/z calc'd. for C₁₁H₄F₄N₅O₂ (M−H)⁻ 314.0306, found 314.0306.

Example 38. Synthesis of 6-((2-Bromo-4-(trifluoromethoxy)phenyl)amino)-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-ol

6-((2-Bromo-4-(trifluoromethoxy)phenyl)amino)-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-ol (1-38) was synthesized by procedure 1-B to yield 1-38 in 5% as a yellow solid: ¹H NMR (400 MHz, Acetone-d₆) δ 11.77 (s, 1H), 9.53 (s, 1H), 8.84 (d, J=9.1 Hz, 1H), 7.80 (d, J=3.7 Hz, 1H), 7.65-7.54 (m, 1H); ¹⁹F NMR (376 MHz, Acetone-d₆) δ-58.97 (s, 3F); ¹³C NMR (101 MHz, Acetone-d₆) δ 153.69, 151.42, 150.07, 146.25 (d, J_(CF)=2.1 Hz), 145.24, 135.55, 126.64 (d, J_(CF)=1.2 Hz), 124.24, 122.39 (d, J_(CF)=1.4 Hz), 121.39 (q, J_(CF)=256.7 Hz), 116.15; HRMS (ESI⁻) m/z calc'd. for C₁₁H₄BrF₃N₅O₃ (M−H)⁻ 389.9455, found 389.9454.

Example 39. Synthesis of 6-((3-Bromo-4-(trifluoromethoxy)phenyl)amino)-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-ol

6-((3-Bromo-4-(trifluoromethoxy)phenyl)amino)-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-ol (1-39) was synthesized by procedure 1-B to yield 1-39 in 34% as a yellow solid: ¹H NMR (400 MHz, Acetone-d₆) δ 11.77 (s, 1H), 9.77 (s, 1H), 8.67 (d, J=2.6 Hz, 1H), 8.26 (dd, J=9.0, 2.6 Hz, 1H), 7.59 (dd, J=9.4, 1.2 Hz, 1H); ¹⁹F NMR (376 MHz, Acetone-d₆) δ-58.54 (s, 3F); ¹³C NMR (101 MHz, Acetone-d₆) δ 153.37, 151.55, 150.10, 145.21, 143.38 (q, J_(CF)=2.1 Hz), 138.87, 126.94, 123.90 (q, J_(CF)=1.5 Hz), 122.77, 121.44 (q, J_(CF)=248.5 Hz), 116.51; HRMS (ESI⁻) m/z calc'd. for C₁₁H₄BrF₃N₅O₃ (M−H)⁻ 389.9455, found 389.9453.

Example 40. Synthesis of 6-((3-Nitro-4-(trifluoromethoxy)phenyl)amino)-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-ol

6-((3-Nitro-4-(trifluoromethoxy)phenyl)amino)-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-ol (1-40). was synthesized by procedure 1-B to yield 1-40 in 2% as a yellow solid: ¹H NMR (400 MHz, Acetone-d₆) δ 10.06 (s, 1H), 9.05 (d, J=2.7 Hz, 1H), 8.61 (dd, J=9.1, 2.7 Hz, 1H), 7.80 (dq, J=9.1, 1.3 Hz, 1H); ¹⁹F NMR (376 MHz, Acetone-d₆) δ-58.76 9 (s, 3F); ¹³C NMR (101 MHz, Acetone-d₆) δ 153.36, 151.89, 149.98, 145.38, 143.70, 138.76, 137.33, 127.69, 125.31 (q, J_(CF)=1.2 Hz), 121.30 (q, J_(CF)=258.5 Hz), 118.97; HRMS (ESI⁻) m/z calc'd. for C₁₁H₄F₃N₆O₅ (M−H)⁻ 357.0200, found 357.0198.

Example 41. Synthesis of 6-((2-Chloro-4-(trifluoromethoxy)phenyl)amino)-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-ol

6-((2-Chloro-4-(trifluoromethoxy)phenyl)amino)-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-ol (1-41) was synthesized by procedure 1-B to yield 1-41 in 9% as a yellow solid: ¹H NMR (400 MHz, Acetone-d₆) δ 13.73 (s, 1H), 9.51 (s, 1H), 8.84 (d, J=9.3 Hz, 1H), 7.66 (d, 1H), 7.58-7.50 (m, 1H); ¹⁹F NMR (376 MHz, Acetone-d₆) δ-58.99 (s, 3F); ¹³C NMR (101 MHz, Acetone-d₆) δ 153.70, 151.40, 150.09, 146.21 (d, J_(CF)=2.4 Hz), 145.27, 134.30, 126.43, 124.37, 123.56 (q, J_(CF)=1.3 Hz), 121.87 (q, J_(CF)=1.1 Hz), 121.39 (q, J_(CF)=256.4, 9.5 Hz); HRMS (ESI⁺) m/z calc'd. for C₁₁H₆ClF₃N₅O₃ (M+H)⁺348.0105, found 348.0089.

Example 42. Synthesis of 6-((3-Fluoro-4-(trifluoromethyl)phenyl)amino)-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-ol

6-((3-Fluoro-4-(trifluoromethyl)phenyl)amino)-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-ol (1-42) was synthesized by procedure 1-B to yield 1-42 in 11% as a yellow solid: ¹H NMR (400 MHz, Acetone-d₆) δ 11.65 (s, 1H), 9.92 (s, 1H), 8.37 (ddd, J=13.4, 2.0, 0.9 Hz, 1H), 8.18-8.12 (m, 1H), 7.82 (d, J=8.5 Hz, 1H); ¹⁹F NMR (376 MHz, Acetone-d₆) δ-61.27 (d, J=12.3 Hz, 3F), −114.54-−114.73 (m, 1F); ¹³C NMR (101 MHz, Acetone-d₆) δ rotamers 160.59 (dq, J=251.6, 2.5 Hz), 153.26*, 153.21, 151.79*, 151.71, 149.95, 145.19, 144.40-144.04 (m), 128.79-128.55 (m), 123.82 (dd, J=270.0, 2.3 Hz), 117.60 (d, J=3.5 Hz)*, 117.51 (d, J=3.6 Hz), 113.87 (dd, J=33.0, 12.8 Hz), 109.79 (d, J=26.3 Hz)*, 109.71 (d, J=26.4 Hz); HRMS (ESI⁻) m/z calc'd. for C₁₁H₄F₄N₅O₂ (M−H)⁻ 314.0306, found 314.0352.

Example 43. Synthesis of 6-((4-Bromo-2-fluorophenyl)amino)-[1,2,5]oxadiazolo[3,4-B]pyrazin-5-ol

6-((4-Bromo-2-fluorophenyl)amino)-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-ol (1-43) was synthesized by procedure 1-B to yield 1-43 in 30% as a yellow solid: ¹H NMR (400 MHz, Acetone-d₆) δ 12.06 (s, 1H), 9.24 (s, 1H), 8.45 (t, J=8.6 Hz, 1H), 7.62-7.51 (m, 2H); ¹³C NMR (101 MHz, Acetone-d₆) δ Rotamers 154.80 (d, J=251.0 Hz), 154.70 (d, J=250.6 Hz)*, 153.36, 153.33*, 151.41, 151.30*, 150.07, 150.06*, 145.12, 128.76 (d, J=4.0 Hz), 128.74 (d, J=4.1 Hz)*, 125.87 (d, J=10.5 Hz), 125.45 (d, J=1.6 Hz), 125.28 (d, J=1.3 Hz)*, 119.71 (d, J=22.6 Hz), 119.69 (d, J=22.7 Hz)*, 118.14 (d, J=9.2 Hz), 118.07 (d, J=9.4 Hz)*; HRMS (ESI⁺) m/z calc'd. for C₁₀H₆BrFN₅O₂ (M+H)⁺325.9683, found 325.9680.

Hydroxy Series with Aliphatic Anilines

Example 44. Synthesis of 6-(Naphthalen-2-ylamino)-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-ol

6-(Naphthalen-2-ylamino)-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-ol (1-44) was synthesized by procedure 1-A to yield 1-44 in 17% as an orange solid: ¹H NMR ((CD₃)₂CO, 500 MHz) δ12.00 (br s, 1H), 9.66 (s, 1H), 8.86 (d, J=2.3 Hz, 1H), 8.07 (dd, J=8.9, 2.3 Hz, 1H), 8.09-7.90 (m, 3H), 7.54 (t, J=7.5 Hz, 1H), 7.49 (t, J=7.5 Hz, 1H); ¹³C NMR ((CD₃)₂CO₃ 126 MHz) δ 153.7, 151.3, 150.5, 145.2, 136.2, 134.7, 132.0, 129.5, 128.8, 128.5, 127.6, 126.4, 122.0, 119.1; HRMS (ESI⁺) m/z calc'd. for C₁₄H₁₀N₅O₂ (M+H)⁺280.0829, found 280.0835.

Example 45. Synthesis of 6-(Methyl(phenyl)amino)-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-ol

6-(Methyl(phenyl)amino)-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-ol (1-45) was synthesized by procedure 1-A to yield 1-45 in 93% as a yellow solid: ¹H NMR ((CD₃)₂CO₃ 400 MHz) δ11.50 (br s, 1H), 7.42-7.37 (m, 2H), 7.34-7.29 (m, 3H), 3.54 (s, 3H); ¹³C NMR ((CD₃)₂CO₃ 126 MHz) δ 154.6, 152.3, 150.6, 147.4, 145.8, 129.8, 127.7, 126.5, 43.5; HRMS (ESI⁻) m/z calc'd. for C₁₁H₈N₅O₂ (M−H)⁻ 242.0683, found 242.0694.

Example 46. Synthesis of 6-((3-Ethylphenyl)amino)-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-ol

6-((3-Ethylphenyl)amino)-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-ol (1-46) was synthesized by procedure 1-A to yield 1-46 in 86% as a yellow solid: ¹H NMR ((CD₃)₂CO₃ 500 MHz) δ12.04 (br s, 1H), 9.42 (br s, 1H), 7.98 (dd, J=8.3, 2.3 Hz, 1H), 7.93 (t, J=2.0 Hz, 1H), 7.36 (t, J=7.9 Hz, 1H), 7.09 (d, J=7.6 Hz, 1H), 2.69 (q, J=7.6 Hz, 2H), 1.25 (t, J=7.6 Hz, 3H); ¹³C NMR ((CD₃)₂CO₃ 126 MHz) δ 153.64, 153.60*, 151.1, 151.0*, 150.5, 145.9, 145.0, 138.64, 138.55*, 129.7, 125.5, 121.5, 121.4*, 119.5, 119.4*, 29.5, 15.9; HRMS (ESI⁻) m/z calc'd. for C₁₂H₁₀N₅O₂ (M−H)⁻256.0840, found 256.0856.

Example 47. Synthesis of 1-(4-((6-Hydroxy-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-yl)amino)phenyl)ethan-1-one

1-(4-((6-Hydroxy-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-yl)amino)phenyl)ethan-1-one (1-47) is synthesized as follows. A round-bottom flask containing 1-2 (0.200 g, 1.05 mmol), 4-aminoacetophenone (0.130 g, 0.962 mmol), and K₂CO₃ (0.200 g, 1.45 mmol) was diluted with acetone/H₂O (9:1, 3 mL) and the resulting dark mixture was stirred at room temperature. After 2 h, the mixture was diluted with a solution of KOH in H₂O (0.320 g in 4 mL) and stirring was continued for an additional 30 min. The mixture was acidified with 1 M HCl and extracted with EtOAc. The organic layer was washed with brine, dried (MgSO₄), and concentrated to a yellow residue. The residue was purified by chromatography on SiO₂ (gradient: 0-2% MeOH/CH₂Cl₂) to yield 1-47 (0.057 g at 93% purity by LC/MS, 19%) as a yellow solid: ¹H NMR ((CD₃)₂CO, 500 MHz) δ 12.13 (br s, 1H), 9.73 (s, 1H), 8.28 (d, J=8.4 Hz, 2H), 8.09 (d, J=8.5 Hz, 2H), 2.60 (s, 3H); ¹³C NMR ((CD₃)₂CO, 126 MHz) δ196.7, 153.5, 151.4, 150.2, 145.2, 142.7, 134.5, 130.2, 121.5, 26.6; HRMS (ES⁺) m/z calc'd. for C₁₂H₁₀N₅O₃ (M+H)+272.0778, found 272.0793.

Example 48. Synthesis of 6-((4-(2-Hydroxyethyl)phenyl)amino)-[1,2,5]oxadiazolo[3,4-B]pyrazin-5-ol

To prepare 6-((4-(2-Hydroxyethyl)phenyl)amino)-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-ol (1-48) a round-bottom flask containing 1-2 (0.200 g, 1.05 mmol) was evacuated and refilled with N2 (3×). The flask was cooled in an ice bath and the solid was sequentially diluted with anhydrous THF (2 mL), a mixture of 2-(4-aminophenyl)ethan-1-ol (0.130 g, 0.948 mmol) in THF (2 mL), and Et₃N (0.15 mL, 1.1 mmol). The mixture, cooled in an ice bath, was stirred for 1.5 h, diluted with EtOAc, filtered through a SiO₂ plug (EtOAc), and concentrated to a residue. The residue was diluted with a solution of KOH (320 mg, 5.70 mmol) in H₂O (4 mL) and THF (2 mL). The resulting solution was stirred at rt for 1 h, acidified with 1 M aq. HCl, and extracted with EtOAc. The organic layer was washed with brine, dried (Na₂SO₄), and concentrated to a pale yellow residue (0.150 g). The residue was purified by chromatography on SiO₂ (gradient: 0-5% MeOH/CH₂Cl₂) to yield product (0.135 g) as an off-white solid at ca. 90% purity by NMR. The solid was diluted with EtOAc and then hexanes for a final mix of ca. 70% EtOAc/hexanes. The solid was filtered, rinsed with hexanes, and collected to yield 1-48 (0.106 g, at 95% purity by NMR, 39%) as a pale yellow solid: ¹H NMR ((CD₃)₂SO, 400 MHz) δ 13.3 (br s, 1H), 10.2 (s, 1H), 7.91-7.88 (m, 2H), 7.26-7.23 (m, 2H), 4.66 (br s, 1H), 3.60 (t, J=7.1 Hz, 2H), 2.72 (t, J=7.1 Hz, 2H); ¹³C NMR ((CD₃)₂CO, 125 MHz) δ 153.7, 151.0, 150.5, 145.1, 137.7, 136.6, 130.3, 122.1, 63.8, 39.8; HRMS (ESI⁻) m/z calc'd. for C₁₂H₁₀N₅O₃ (M−H) 272.0789, found 272.0796.

Example 49. Synthesis of 6-((4-(Methylsulfonyl)phenyl)amino)-[1,2,5]oxadiazolo[3,4-B]pyrazin-5-ol

6-((4-(Methylsulfonyl)phenyl)amino)-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-ol (1-49) was synthesized by procedure 1-A to yield 1-49 in 40% as a light yellow solid: ¹H NMR ((CD₃)₂SO, 500 MHz) δ 13.37 (br s, 1H), 10.60 (s, 1H), 8.31 (d, J=8.8 Hz, 2H), 7.96 (d, J=8.8 Hz, 2H), 3.21 (s, 3H); ¹³C NMR ((CD₃)₂SO, 125 MHz) δ 152.9, 151.3, 149.5, 144.7, 142.3, 136.0, 127.9, 121.7, 43.7; HRMS (ESI⁻) m/z calc'd. for C₁₁H₈N₅O₄S (M−H)⁻306.0302, found 306.0307.

Example 50. Synthesis of 6-(Naphthalen-1-ylamino)-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-ol

6-(Naphthalen-1-ylamino)-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-ol (1-50) was synthesized by procedure 1-A to yield 1-50 in 46% as a yellow solid: ¹H NMR ((CD₃)₂CO, 500 MHz) δ 12.10 (br s, 1H), 9.77 (s, 1H), 8.14 (d, J=7.5 Hz, 1H), 8.09-8.07 (m, 1H), 8.02-8.00 (m, 1H), 7.90 (d, J=8.2, 1H), 7.64-7.57 (m, 3H); ¹³C NMR ((CD₃)₂CO, 125 MHz) δ 153.9, 152.9, 150.7, 145.3, 135.2, 133.5, 129.5, 129.0, 127.7, 127.4, 127.2, 126.5, 123.0, 122.7; HRMS (ESI⁻) m/z calc'd. for C₁₄H₈N₅O₂ (M−H)⁻ 278.0683, found 278.0689.

Example 51. Synthesis of 6-((4-(tert-Butyl)phenyl)amino)-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-ol

6-((4-(tert-Butyl)phenyl)amino)-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-ol (1-51) was synthesized by procedure 1-B to yield 1-51 in 64% as a tan solid: ¹H NMR (400 MHz, Acetone-d₆) δ 11.98 (s, 1H), 9.44 (s, 1H), 8.24-7.79 (m, 2H), 7.71-7.27 (m, 2H), 1.34 (s, 9H); ¹³C NMR (101 MHz, Acetone-d₆) δ 152.75, 150.06, 149.60, 147.89, 144.12, 135.14, 125.59, 120.98, 34.14, 30.72; HRMS (ESI⁺) m/z calc'd. for C₁₄H₁₆N₅O₂ (M+H)⁺286.12985, found 286.1289.

Example 52. Synthesis of 6-((4-(tert-Butyl)phenyl)amino)-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-ol

6-(Phenylamino)-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-ol (1-52) was synthesized by procedure 1-B to yield 1-52 in 39% as a yellow solid: ¹H NMR (400 MHz, Acetone-d₆) δ 12.04 (s, 1H), 9.50 (s, 1H), 8.16-8.08 (m, 2H), 7.50-7.42 (m, 2H), 7.27-7.19 (m, 1H); ¹³C NMR (126 MHz, DMSO-d₆) δ 153.04, 150.77, 149.69, 144.53, 137.78, 128.65, 124.82, 121.83; HRMS (ESI⁺) m/z calc'd. for C₁₀H₈N₅O₂ (M+H)⁺230.0672, found 230.0671.

Example 53. Synthesis of 6-((3-(tert-Butyl)phenyl)amino)-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-ol

6-((3-(tert-Butyl)phenyl)amino)-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-ol (1-53) was synthesized by procedure 1-B to yield 1-53 in 47% as a yellow solid: ¹H NMR (400 MHz, Acetone-d₆) δ 11.93 (s, 1H), 9.53-9.41 (m, 1H), 8.11-8.05 (m, 2H), 7.41-7.35 (m, 1H), 7.31-7.25 (m, 1H), 1.35 (d, J=0.6 Hz, 9H); ¹³C NMR (101 MHz, Acetone-d₆) δ 153.65, 152.82, 151.03, 150.46, 145.01, 138.40, 129.39, 122.89, 119.43, 119.19, 35.42, 31.57; HRMS (ESI⁻) m/z calc'd. for C₁₄H₁₄N₅O₂ (M−H)⁻ 284.1153, found 284.1152.

Examples 54. Synthesis of 6-((4-Butylphenyl)amino)-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-ol

6-((4-Butylphenyl)amino)-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-ol (1-54) was synthesized by procedure 1-B to yield 1-54 in 33% as a yellow solid: ¹H NMR (400 MHz, Acetone-d₆) δ12.04 (s, 1H), 9.42 (s, 1H), 8.25-7.74 (m, 2H), 7.50-7.01 (m, 2H), 2.67-2.58 (m, 2H), 1.66-1.55 (m, 2H), 1.43-1.30 (m, 2H), 0.93 (t, J=7.4 Hz, 3H); ¹³C NMR (101 MHz, Acetone-d₆) δ Rotamers z153.55, 153.51*, 150.82, 150.73*, 150.43, 144.91, 140.56, 136.23, 136.14*, 129.51, 122.02, 121.93*, 35.64, 34.42, 22.91, 14.17; HRMS (ESI⁺) m/z calc'd. for C₁₄H₁₆N₅O₂ (M+H)⁺286.1298, found 286.1307.

Example 55. Synthesis of 6-((4-Butyl-2-fluorophenyl)amino)-[1,2,5]oxadiazolo[3,4-B]pyrazin-5-ol

6-((4-Butyl-2-fluorophenyl)amino)-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-ol (1-55) was synthesized by procedure 1-B to yield 1-55 in 21% as a yellow solid: ¹H NMR (400 MHz, Acetone-d₆) δ 12.13 (s, 1H), 9.19 (s, 1H), 8.41-8.33 (m, 1H), 7.20-7.14 (m, 2H), 2.72-2.62 (t, 2H), 1.69-1.58 (m, 2H), 1.44-1.31 (m, 2H), 0.94 (t, J=7.4 Hz, 3H); ¹⁹F NMR (376 MHz, Acetone-d₆) δ-129.46-−129.54 (m); HRMS (ESI⁺) m/z calc'd. for C₁₄H₁₅FN₅O₂ (M+H)⁺304.1204, found 304.1207.

Examples 56. Synthesis of 6-((2,6-Dimethylphenyl)amino)-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-ol

6-((2,6-Dimethylphenyl)amino)-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-ol (1-56) was synthesized by procedure 1-B to yield 1-56 in 39% as a yellow solid: ¹H NMR (400 MHz, Acetone-d₆) δ 11.97 (s, 1H), 9.25 (s, 1H), 7.21-7.13 (m, 3H), 2.26 (s, 6H); ¹³C NMR (101 MHz, Acetone-d₆) δ153.49, 152.87, 150.97, 145.40, 136.69, 135.23, 128.88, 128.53, 18.45; HRMS (ESI⁺) m/z calc'd. for C₁₂H₁₂N₅O₂ (M+H)⁺258.0985, found 258.0993.

Example 57. Synthesis of 3-((6-Hydroxy-[1,2,5]Ooxadiazolo[3,4-b]pyrazin-5-yl)amino)benzonitrile

3-((6-Hydroxy-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-yl)amino)benzonitrile (1-57) was synthesized by procedure 1-B to yield 1-57 in 17% as a yellow solid: ¹H NMR (400 MHz, Acetone-d₆) δ 12.09 (s, 1H), 9.78 (s, 1H), 8.63-8.59 (m, 1H), 8.42 (dd, J=8.3, 1.1 Hz, 1H), 7.69 (dd, J=7.9, 0.5 Hz, 1H), 7.62 (dd, J=7.9, 1.3 Hz, 1H); ¹³C NMR (101 MHz, Acetone-d₆) δ153.39, 151.67, 150.14, 145.19, 139.68, 131.13, 129.13, 126.56, 125.02, 119.11, 113.61; HRMS (ESI⁺) m/z calc'd. for C₁₁H₇N₆O₂ (M+H)⁺255.0625, found 255.0639.

Example 58. Synthesis of 6-(p-Tolylamino)-[1,2,5]Ooxadiazolo[3,4-b]pyrazin-5-ol

6-(p-Tolylamino)-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-ol (1-58) was synthesized by procedure 1-B to yield 1-58 in 39% as a yellow solid: ¹H NMR (400 MHz, Acetone-d₆) δ11.96 (s, 1H), 9.42 (s, 1H), 7.98 (d, J=8.6 Hz, 2H), 7.26 (d, J=8.4 Hz, 2H), 2.34 (s, 3H); ¹³C NMR (101 MHz, Acetone-do) δ 153.66, 150.94, 150.50, 145.05, 136.14, 135.52, 130.17, 122.05, 20.94; HRMS (ESI⁺) m/z calc'd. for C₁₁H₁₀N₅O₂ (M+H)⁺244.0829, found 244.0812.

Example 59. Synthesis of 6-(Mesitylamino)-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-ol

6-(Mesitylamino)-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-ol (1-59) was synthesized by procedure 1-B to yield 1-59 in 25% as a colorless solid: ¹H NMR (400 MHz, Acetone-d₆) δ11.83 (s, 1H), 9.17 (s, 1H), 6.96 (s, 2H), 2.28 (s, 3H), 2.21 (s, 6H); ¹³C NMR (101 MHz, Acetone-d₆) δ153.62, 153.03, 151.10, 145.48, 138.10, 136.36, 132.66, 129.61, 21.07, 18.44; HRMS (ESI⁻) m/z calc'd. for C₁₃H₁₂N₅O₂ (M−H)⁻ 270.0996, found 270.0992.

Example 60. Synthesis of 6-((3,4-Dimethylphenyl)Aamino)-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-ol

6-((3,4-Dimethylphenyl)amino)-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-ol (1-60) was synthesized by procedure 1-B to yield 1-60 in 48% as a yellow solid: ¹H NMR (400 MHz, Acetone-d₆) δ 11.93 (s, 1H), 9.32 (s, 1H), 7.86 (dd, J=8.2, 2.4 Hz, 1H), 7.81 (d, J=2.4 Hz, 1H), 7.19 (d, J=8.2 Hz, 1H), 2.27 (d, J=12.0 Hz, 6H); ¹³C NMR (101 MHz, Acetone-d₆) δ 153.74, 150.93, 150.60, 145.10, 137.89, 136.45, 134.36, 130.75, 123.21, 119.62, 20.06, 19.34. HRMS (ESI⁻) m/z calc'd. for C₁₂H₁₀N₅O₂ (M−H)⁻256.0840, found 256.0847.

Example 61. Synthesis of 6-((4-Ethylphenyl)amino)-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-ol

6-((4-Ethylphenyl)amino)-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-ol (1-61) was synthesized by procedure 1-B to yield 1-61 in 56% as a yellow solid. ¹H NMR (400 MHz, Acetone-d₆) δ11.92 (s, 1H), 9.44 (s, 1H), 8.07-7.94 (m, 2H), 7.33-7.26 (m, 2H), 2.66 (q, J=7.6 Hz, 2H), 1.23 (t, J=7.6 Hz, 3H); ¹³C NMR (101 MHz, Acetone-d₆) δ 153.62, 153.58*, 150.93, 150.83*, 150.48, 145.00, 142.00, 141.99*, 136.30, 136.21, 129.00, 122.15, 122.06, 28.91, 16.04; HRMS (ESI⁺) m/z calc'd. for C₁₂H₁₂N₅O₂ (M+H)⁺258.0985, found 258.0984.

Example 62. Synthesis of 6-((2-Fluoro-4-(pent-1-yn-1-yl)phenyl)amino)-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-ol Step 1. Synthesis of 2-Fluoro-4-(pent-1-yn-1-yl)aniline (1-62-int)

Compound 1-62-int was synthesized by procedure 1-H to yield crude 1-62-int that was used without further purification: ¹H NMR (400 MHz, Acetone-d₆) δ 6.99-6.91 (m, 2H), 6.80-6.74 (m, 1H), 4.91 (s, 2H), 2.33 (t, J=7.0 Hz, 2H), 1.56 (h, 2H), 1.01 (t, J=7.6, 7.1 Hz, 3H); ¹⁹F NMR (376 MHz, Acetone-d₆) δ−137.21-−137.30 (m, 1F); ¹³C NMR (101 MHz, Acetone-d₆) δ 151.26 (d, J_(CF)=237.2 Hz), 137.35 (d, J_(CF)=12.8 Hz), 129.06 (d, J_(CF)=3.0 Hz), 118.59 (d, J_(CF)=19.7 Hz), 116.98 (d, J_(CF)=5.0 Hz), 112.95 (d, J_(CF)=8.3 Hz), 88.12, 81.20 (d, J_(CF)=2.9 Hz), 23.11, 21.74, 13.80.

Step 2. Synthesis of 6-((2-Fluoro-4-(pent-1-yn-1-yl)phenyl)amino)-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-ol (1-62)SHG2061819)

Compound 1-62 was synthesized by procedure 1-B with 1-62-int to yield 1-62 in 27% as a yellow solid: ¹H NMR (400 MHz, Acetone-d₆) δ 11.90 (s, 1H), 9.22 (s, 1H), 8.53 (t, J=8.5 Hz, 1H), 7.41-7.26 (m, 2H), 2.42 (t, J=7.0 Hz, 2H), 1.62 (h, J=7.2 Hz, 2H), 1.04 (t, J=7.4 Hz, 3H); ¹⁹F NMR (376 MHz, Acetone-d₆) δ−129.49-−129.66 (m, 1F); ¹³C NMR (126 MHz, Acetone-d₆) δ154.23 (d, J=246.3 Hz), 153.58, 151.26, 150.23, 145.24, 128.99 (d, J=3.3 Hz), 126.19 (d, J=10.4 Hz), 123.59, (d, J=9.5 Hz), 118.81 (d, J=20.7 Hz), 92.48, 80.15 (d, J=2.9 Hz), 22.83, 21.71, 13.80; HRMS (ESI⁺) m/z calc'd. for C₁₅H₁₃FN₅O₂ (M+H)⁺314.1047, found 314.1045.

Example 63. Synthesis of 6-((2-Fluoro-4-(hex-1-yn-1-yl)phenyl)amino)-[1,2,5]oxadiazolo[3,4-B]pyrazin-5-ol Step 1. Synthesis of 2-Fluoro-4-(hex-1-yn-1-yl)aniline (1-63-int)

Compound 1-63-int. was synthesized by procedure 1-H to yield crude 1-63-int that was used without further purification: ¹H NMR (400 MHz, Acetone-d₆) δ 6.99-6.91 (m, 2H), 6.80-6.73 (m, 1H), 4.91 (s, 2H), 2.36 (t, J=6.9 Hz, 2H), 1.59-1.40 (m, 4H), 0.92 (t, J=7.2 Hz, 3H); ¹⁹F NMR (376 MHz, Acetone-d₆) δ−137.20-−137.30 (m, 1F); ¹³C NMR (101 MHz, Acetone-d₆) δ 151.27 (d, J_(CF)=237.3 Hz), 137.35 (d, J_(CF)=12.8 Hz), 129.07 (d, J_(CF)=2.7 Hz), 118.60 (d, J_(CF)=19.5 Hz), 116.98 (d, J_(CF)=5.0 Hz), 112.98 (d, J_(CF)=8.4 Hz), 88.26, 81.05 (d, J_(CF)=2.7 Hz), 31.87, 22.69, 19.47, 13.98; HRMS (ESI⁺) m/z calc'd. for C₁₂H₁₅FN (M+H)⁺192.1183, found 192.1177.

Step 2. Synthesis of 6-((2-Fluoro-4-(hex-1-yn-1-yl)phenyl)amino)-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-ol (1-63)

Compound 1-63 was synthesized by procedure 1-B with 1-63-int to yield 1-63 in 29% as a yellow solid: ¹H NMR (400 MHz, Acetone-d₆) δ 12.16 (s, 1H), 9.24 (s, 1H), 8.53 (t, 1H), 7.39-7.29 (m, 2H), 2.45 (t, J=7.0 Hz, 2H), 1.64-1.44 (m, 4H), 0.95 (t, J=7.3 Hz, 3H); ¹⁹F NMR (376 MHz, Acetone-d₆) δ Rotamers −129.46-−129.60 (m), −129.71-−129.83 (m); ¹³C NMR (126 MHz, Acetone-d₆) δ 154.24 (d, J_(CF)=246.3 Hz), 153.61, 151.27, 150.24, 145.27, 128.99 (d, J_(CF)=3.8 Hz), 126.19 (d, J_(CF)=10.6 Hz), 123.60 (d, J_(CF)=1.6 Hz), 122.74 (d, J_(CF)=9.8 Hz), 118.81 (d, J_(CF)=20.7 Hz), 92.63, 80.01 (d, J_(CF)=3.5 Hz), 31.54, 22.71, 19.48, 13.96; HRMS (ESI⁺) m/z calc'd. C₁₆H15FN₅O₂ (M+H)⁺328.1204, found 328.1215.

Example 64. Synthesis of 6-((4-(Pent-1-yn-1-yl)-2-(trifluoromethoxy)phenyl)amino)-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-ol Step 1. Synthesis of 4-(Pent-1-yn-1-yl)-2-(trifluoromethoxy)aniline (1-64-int)

Compound 1-64-int was synthesized by procedure 1-H to yield crude 1-64-int that was used without further purification: ¹H NMR (400 MHz, Acetone-d₆) δ 7.15-7.08 (m, 2H), 6.84 (d, J=8.3 Hz, 1H), 5.27-5.12 (m, 2H), 2.34 (t, J=7.0 Hz, 2H), 1.57 (h, 2H), 1.01 (t, J=7.4 Hz, 3H); ¹⁹F NMR (376 MHz, Acetone-d₆) δ−58.70 (s, 3F); ¹³C NMR (101 MHz, Acetone-d₆) δ 140.96, 134.67, 131.15, 124.47, 120.97 (q, J_(CF)=256.0 Hz), 116.26, 111.84, 87.50, 79.82, 22.08, 20.72, 12.80; HRMS (ESI⁺) m/z calc'd. for C₁₂H₁₃F₃NO (M+H)⁺244.0943, found 244.0944.

Step 2. Synthesis of 6-((4-(Pent-1-yn-1-yl)-2-(trifluoromethoxy)phenyl)amino)-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-ol

Compound 1-64 was synthesized by procedure 1-B with 1-64-int to yield 1-64 in 44% as a yellow solid:¹H NMR (400 MHz, Acetone-d₆) δ12.06 (s, 1H), 9.35 (s, 1H), 8.76 (d, J=8.6 Hz, 1H), 7.56 (dd, J=8.6, 1.8 Hz, 1H), 7.48 (p, J=1.7 Hz, 1H), 2.43 (t, J=7.0 Hz, 2H), 1.63 (h, J=7.5 Hz, 2H), 1.05 (t, J=7.4 Hz, 3H); ¹⁹F NMR (376 MHz, Acetone-d₆) δ-58.59 (s, 3F); ¹³C NMR (126 MHz, Acetone-d₆) δ 153.73, 151.18, 150.16, 145.27, 139.92 (q, J_(CF)=1.8 Hz), 132.07, 130.48, 124.51, 123.23, 122.39, 121.57 (q, J_(CF)=258.7 Hz), 93.00, 79.88, 22.82, 21.74, 13.83; HRMS (ESI⁺) m/z calc'd. for C₁₆H₁₃F₃N₅O₃ (M+H)⁺380.0965, found 380.0947.

Example 65. Synthesis of 6-((4-(Hex-1-yn-1-yl)-2-(trifluoromethoxy)phenyl)amino)-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-ol Step 1. Synthesis of 4-(Hex-1-yn-1-yl)-2-(trifluoromethoxy)aniline (1-65-int)

Compound 1-65-int was synthesized by procedure 1-H to yield crude 1-65-int that was used without further purification: ¹H NMR (400 MHz, Acetone-d₆) δ 7.14-7.07 (m, 2H), 6.83 (d, 1H), 5.20 (s, 2H), 2.37 (t, J=6.9 Hz, 2H), 1.59-1.40 (m, 4H), 0.93 (t, J=7.2 Hz, 3H); ¹⁹F NMR (376 MHz, Acetone-d₆) δ-58.69 (s, 3F); ¹³C NMR (101 MHz, Acetone-d₆) δ 141.98, 135.71, 132.18, 125.49, 122.01 (q, J_(CF)=256.0 Hz), 117.30, 112.90, 88.67, 80.70, 31.85, 22.72, 19.48, 13.99, HRMS (ESI⁺) m/z calc'd. for C₁₃H₁₅F₃NO (M+H)⁺258.1100, found 258.1092.

Step 2. 6-((4-(Hex-1-yn-1-yl)-2-(trifluoromethoxy)phenyl)amino)-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-ol

(1-65) was synthesized by procedure 1-B with 1-65-int to yield 1-65 in 51% as a yellow solid: ¹H NMR (400 MHz, Acetone-d₆) δ 12.03 (s, 1H), 9.35 (s, 1H), 8.76 (d, J=8.6 Hz, 1H), 7.56 (dd, J=8.6, 1.8 Hz, 1H), 7.48 (p, J=1.7 Hz, 1H), 2.46 (t, J=7.0 Hz, 2H), 1.65-1.44 (m, 4H), 0.95 (t, J=7.3 Hz, 3H); ¹⁹F NMR (376 MHz, Acetone-d₆) δ−58.59 (s, 3F); ¹³C NMR (126 MHz, Acetone-d₆) δ 153.74, 151.18, 150.17, 145.28, 139.93 (q, J_(CF)=2.0 Hz), 132.07, 130.47, 124.50 (q, J_(CF)=1.8 Hz), 123.23, 122.41, 121.57 (q, J_(CF)=259.0 Hz), 93.15, 79.73, 31.53, 22.74, 19.50, 13.97; HRMS (ESI⁺) m/z calc'd. for C₁₇H₁₅F₃N₅O₃ (M+H)⁺394.1121, found 394.1113.

Example 66. Synthesis of 6-((2-Fluoro-4-pentylphenyl)amino)-[1,2,5]oxadiazolo[3,4-B]pyrazin-5-ol Step 1. Synthesis of 2-Fluoro-4-pentylaniline (1-66-int)

Compound 1-66-int was synthesized by procedure 1-I with 1-62-int to yield crude 1-66-int that was used without further purification: ¹H NMR (400 MHz, Acetone-d₆) δ 6.84-6.70 (m, 3H), 4.42 (s, 2H), 2.47 (t, J=7.8 Hz, 2H), 1.60-1.49 (m, 2H), 1.37-1.24 (m, 4H), 0.87 (t, J=7.0 Hz, 3H); ¹⁹F NMR (376 MHz, Acetone-d₆) δ−137.49-−137.62 (m, 1F); ¹³C NMR (101 MHz, Acetone-d₆) δ 152.29 (d, J_(CF)=236.4 Hz), 132.93, 126.01, 125.10 (d, J_(CF)=2.8 Hz), 117.44 (d, J_(CF)=4.4 Hz), 115.55 (d, J_(CF)=18.4 Hz), 35.51 (d, J_(CF)=1.5 Hz), 32.27, 32.20, 23.29, 14.42; HRMS (ESI⁺) m/z calc'd. for C₁₁H₁₇FN (M+H)⁺182.1339, found 182.1336.

Step 2. Synthesis of 6-((2-Fluoro-4-pentylphenyl)amino)-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-ol

Compound 1-66 was synthesized by procedure 1-B with 1-66-int to yield 1-66 in 37% as a yellow solid: ¹H NMR (400 MHz, Acetone-d₆) δ 11.96 (s, 1H), 9.17 (s, 1H), 8.37 (q, 1H), 7.20-7.13 (m, 2H), 2.66 (t, 2H), 1.72-1.60 (m, 2H), 1.40-1.30 (m, 4H), 0.89 (t, 3H); ¹⁹F NMR (376 MHz, Acetone-d₆) δ Rotamers −129.56-−129.65 (m, 1F), −129.80-−129.89 (m, 1F); ¹³C NMR (126 MHz, Acetone-d₆) δ 154.97 (d, J_(CF)=245.6 Hz), 153.63, 151.34, 150.37, 145.20, 143.02 (d, J_(CF)=7.1 Hz), 125.38 (d, J_(CF)=3.2 Hz), 124.04, 123.83 (d, J_(CF)=10.8 Hz), 115.96 (d, J_(CF)=18.9 Hz), 35.87 (d, J_(CF)=1.5 Hz), 32.14, 31.72, 23.18, 14.33; HRMS (ESI⁺) m/z calc'd. for C₁₅H₁₇FN₅O₂ (M+H)⁺318.1360, found 318.1365.

Example 67. Synthesis of 6-((2-Fluoro-4-hexylphenyl)amino)-[1,2,5]oxadiazolo[3,4-B]pyrazin-5-ol Step 1. Synthesis of 2-Fluoro-4-hexylaniline (1-67-int)

Compound 1-67 int was synthesized by procedure 1-I to yield crude 1-67-int that was used without further purification: ¹H NMR (400 MHz, Acetone-d₆) δ6.83-6.71 (m, 3H), 4.42 (s, 2H), 2.47 (t, J=7.9, 7.4 Hz, 2H), 1.59-1.49 (m, 2H), 1.36-1.25 (m, 6H), 0.87 (t, J=7.0 Hz, 3H); ¹⁹F NMR (376 MHz, Acetone-d₆) δ−137.42-−137.67 (m, 1F); ¹³C NMR (101 MHz, Acetone-d₆) δ 152.28 (d, J_(CF)=236.1 Hz), 134.59 (d, J_(CF)=13.0 Hz), 132.91 (d, J_(CF)=6.0 Hz), 125.10 (d, J_(CF)=3.1 Hz), 117.44 (d, J_(CF)=4.6 Hz), 115.55 (d, J_(CF)=18.4 Hz), 35.54 (d, J_(CF)=1.5 Hz), 32.55, 29.65, 23.39, 14.45; HRMS (ESI⁺) m/z calc'd. for C₁₂H₁₉FN (M+H)⁺196.1496, found 196.1496.

Step 2. Synthesis of 6-((2-Fluoro-4-hexylphenyl)amino)-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-ol (1-67) (SHG2061822)

Compound 1-67 was synthesized by procedure 1-B with 1-67-int to yield 1-67 in 50% as a yellow solid: ¹H NMR (400 MHz, Acetone-d₆) δ 11.91 (s, 1H), 9.16 (s, 1H), 8.35 (t, J=8.3 Hz, 1H), 7.19-7.13 (m, 2H), 2.66 (t, J=7.6 Hz, 2H), 1.70-1.60 (m, 2H), 1.41-1.26 (m, 6H), 0.89 (t, 3H); ¹⁹F NMR (376 MHz, Acetone-d₆) δ Rotamers −129.58-−129.71 (m, 1F), −129.83-−129.92 (m, 1F); ¹³C NMR (101 MHz, Acetone-d₆) δ 154.91 (d, J_(CF)=245.6 Hz), 153.58, 151.27, 150.33, 145.15, 142.97 (d, J_(CF)=7.0 Hz), 125.35 (d, J_(CF)=3.1 Hz), 123.96, 123.80 (d, J_(CF)=10.7 Hz), 115.92 (d, J_(CF)=18.7 Hz), 35.89 (d, J_(CF)=1.4 Hz), 32.40, 31.97, 29.60, 23.28, 14.37; HRMS (ESI⁺) m/z calc'd. for C₁₆H₁₉FN₅O₂ (M+H)⁺332.1517, found 332.1515.

Example 68. Synthesis of 6-((4-Ethyl-2-fluorophenyl)amino)-[1,2,5]oxadiazolo[3,4-B]pyrazin-5-Ol. (1-68)

Compound 1-68 was synthesized by procedure 1-B to yield 1-68 in 33% as a yellow solid: ¹H NMR (400 MHz, Acetone-d₆) δ 11.54 (s, 1H), 9.17 (s, 1H), 8.35 (t, J=8.3 Hz, 1H), 7.23-7.13 (m, 2H), 2.69 (q, J=7.6 Hz, 2H), 1.25 (t, J=7.6 Hz, 3H); ¹⁹F NMR (376 MHz, Acetone-d₆) δ Rotamers −129.38-−129.48 (m, 1F), −129.63-−129.71 (m, 1F); ¹³C NMR (101 MHz, Acetone-d₆) δ155.05 (d, J_(CF)=245.5 Hz), 153.63, 151.37, 150.37, 145.21, 144.37 (d, J_(CF)=6.9 Hz), 124.81 (d, J_(CF)=3.4 Hz), 124.11 (d, J_(CF)=16.1 Hz), 123.81 (d, J_(CF)=10.7 Hz), 115.47 (d, J_(CF)=19.0 Hz), 28.89 (d, J_(CF)=1.6 Hz), 15.75; HRMS (ESI⁺) m/z calc'd. for C₁₂H₁₁FN₅O₂ (M+H)⁺276.0891, found 276.0893.

Example 69. Synthesis of 6-((4-Pentyl-2-(trifluoromethoxy)phenyl)amino)-[1,2,5]Ooxadiazolo[3,4-b]pyrazin-5-ol (1-69) Step 1. Synthesis of 4-pentyl-2-(trifluoromethoxy)aniline (1-69-int)

Compound 1-69-int was synthesized by procedure 1-I with 1-64-int to yield crude 1-69-int that was used without further purification: ¹H NMR (400 MHz, Acetone-d₆) δ 6.98-6.89 (m, 2H), 6.81 (d, J=8.1 Hz, 1H), 4.70 (s, 2H), 2.50 (t, 2H), 1.61-1.51 (m, 2H), 1.39-1.25 (m, 4H), 0.87 (t, 3H); ¹⁹F NMR (376 MHz, Acetone-d₆) δ-58.40 (s, 1F), −58.80 (s, 1F); ¹³C NMR (101 MHz, Acetone-d₆) δ 145.31, 138.55, 131.56, 127.70, 121.20, 121.09 (q, J=255.2 Hz), 116.62, 34.38, 31.26, 31.14, 22.24, 13.39; HRMS (ESI⁺) m/z calc'd. for C₁₂H₁₇F₃NO⁺ (M+H)⁺248.1256, found 248.1251.

Step 2: Synthesis of 6-((4-Pentyl-2-(trifluoromethoxy)phenyl)amino)-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-ol (1-69)

Compound 1-69 was synthesized by procedure 1-B with 1-69-int to yield 1-69 in 47% as a yellow solid:¹H NMR (400 MHz, Acetone-d₆) δ12.19 (s, 1H), 9.28 (s, 1H), 8.61 (d, J=8.5 Hz, 1H), 7.42-7.34 (m, 2H), 2.71 (t, J=7.9 Hz, 2H), 1.72-1.62 (m, 2H), 1.40-1.30 (m, 4H), 0.89 (t, J=6.9 Hz, 3H); ¹⁹F NMR (376 MHz, Acetone-d₆) δ Rotamers −58.42 (d, J=1.3 Hz, 1F), −58.44 (d, J=1.3 Hz, 1F); ¹³C NMR (101 MHz, Acetone-d₆) δ152.72, 150.16, 149.32, 144.22, 141.47, 139.43, 127.78 (q, J_(CF)=1.5 Hz), 127.39, 122.55, 120.85 (q, J_(CF)=259.2 Hz), 120.82, 34.86, 31.16, 30.85, 22.21, 13.37; HRMS (ESI⁺) m/z calc'd. for C₁₆H₁₇F₃N₅O₃ (M+H)⁺384.1278, found 384.1296.

Example 70. Synthesis of 6-((4-hexyl-2-(trifluoromethoxy)pPhenyl)amino)-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-ol (1-70) Step 1. Synthesis of 4-Hexyl-2-(trifluoromethoxy)aniline (1-70-int)

Compound 1-70-int was synthesized by procedure 1-I with 1-65-int to yield crude 1-70-int that was used without further purification: ¹H NMR (400 MHz, Acetone-d₆) δ 6.98-6.90 (m, 2H), 6.81 (d, J=8.2 Hz, 1H), 4.69 (s, 2H), 2.49 (t, J=7.9 Hz, 2H), 1.61-1.50 (m, 2H), 1.35-1.25 (m, 6H), 0.87 (t, 3H); ¹⁹F NMR (376 MHz, Acetone-d₆) δ-58.37 (s, 1F); HRMS (ESI⁺) m/z calc'd. for C₁₃H₁₉F₃NO (M+H)⁺262.1413, found 262.1408.

Step 2. Synthesis of 6-((4-hexyl-2-(trifluoromethoxy)phenyl)amino)-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-ol (1-70)

Compound 1-70 was synthesized by procedure 1-B with 1-70-int to yield 1-70 in 14% as a yellow solid: ¹H NMR (400 MHz, Acetone-d₆) δ 12.14 (s, 1H), 9.27 (s, 1H), 8.60 (d, J=8.3 Hz, 1H), 7.42-7.34 (m, 2H), 2.71 (t, J=7.4 Hz, 2H), 1.72-1.60 (m, 2H), 1.39-1.28 (m, 6H), 0.87 (t, J=7.0 Hz, 3H); ¹⁹F NMR (376 MHz, Acetone-d₆) δ−58.31 (d, J=1.9 Hz, 3F), −58.39 (d, J=1.8 Hz, 3F), ¹³C NMR (126 MHz, Acetone-d₆) δ 153.80, 151.27, 150.34, 145.27, 142.53, 140.54 (q, J=2.4 Hz), 128.78, 128.48, 123.71, 121.84, 121.67 (q, J=258.0 Hz), 35.91, 32.45, 32.13, 29.61, 23.35, 14.41; HRMS (ESI⁺) m/z calc'd. for C₁₇H₁₉F₃N₅O₃ (M+H)⁺398.1434, found 398.1441.

Example 71. Synthesis of 6-((4-Pentylphenyl)amino)-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-ol (1-71)

Compound 1-71 was synthesized by procedure 1-B to yield 1-71 in 55% as a yellow solid: ¹H NMR (400 MHz, Acetone-d₆) δ 11.95 (s, 1H), 9.43 (s, 1H), 8.05-7.97 (m, 2H), 7.31-7.24 (m, 2H), 2.63 (t, J=7.7 Hz, 2H), 1.69-1.58 (m, 2H), 1.42-1.28 (m, 4H), 0.89 (t, 3H); ¹³C NMR (101 MHz, Acetone-d₆) δ 153.66, 150.92, 150.51, 145.03, 140.67, 136.32, 129.58, 122.09, 35.97, 32.19, 32.00, 23.19, 14.34; HRMS (ESI⁺) m/z calc'd. for C₁₅H₁₈N₅O₂ (M+H)⁺300.1455, found 300.1443.

Example 72. Synthesis of 6-((4-Hexylphenyl)amino)-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-ol (1-72)

Compound 1-72 was synthesized by procedure 1-B to yield 1-72 in 40% as a yellow solid: ¹H NMR (400 MHz, Acetone-d₆) δ 11.98 (s, 1H), 9.43 (s, 1H), 8.04-7.97 (m, 2H), 7.31-7.25 (m, 2H), 2.63 (t, J=7.5 Hz, 2H), 1.69-1.57 (m, 2H), 1.41-1.25 (m, 6H), 0.88 (t, J=6.9 Hz, 3H); ¹³C NMR (101 MHz, Acetone-d₆) δ 153.68, 150.96, 150.54, 145.06, 140.70, 136.35, 129.62, 122.11, 36.03, 32.48, 32.32, 29.70, 23.33, 14.39; HRMS (ESI⁺) m/z calc'd. for C₁₆H₂₀N₅O₂ (M+H)⁺314.1611, found 314.1602.

Hydroxy Series with Alkyl Amines

Example 73. Synthesis of 6-(Isopropylamino)-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-ol (1-73)

Compound 1-73 was synthesized by procedure 1-B to yield 1-73 in 60% as a tan solid: 1H NMR (400 MHz, Acetone-d₆) δ 11.44 (s, 1H), 7.59 (s, 1H), 4.56-4.11 (m, 1H), 1.31 (d, J=6.6 Hz, 6H); ¹³C NMR (101 MHz, Acetone-d₆) δ153.31, 152.53, 150.88, 144.81, 44.03, 21.68; HRMS (ESI⁺) m/z calc'd. for C₇H₁₀N₅O₂ (M+H)⁺196.0829, found 196.0826.

Example 74. Synthesis of 6-(Octylamino)-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-ol (1-74)

A round-bottom flask containing 1-2 (0.200 g, 1.05 mmol) and K₂CO₃ (0.200 g, 1.45 mmol) in acetone/H₂O (9:1, 3 mL) was slowly diluted with a solution of n-octylamine (0.125 g, 0.967 mmol) in acetone/H₂O (9:1, 1 mL) and the resulting dark mixture was stirred at rt. After 2 h, the mixture was diluted with a solution of KOH in H₂O (0.320 g in 4 mL) and stirring was continued for an additional 30 min. The mixture was acidified with 1 M HCl and extracted with EtOAc. The organic layer was washed with brine, dried (MgSO₄), and concentrated to a brown residue. The residue was purified by chromatography on SiO₂ (gradient: 0.5-2% MeOH/CH₂Cl₂) to yield a crude brown solid. The solid was dissolved in EtOAc and extracted with 2-3 M NaOH. The aqueous layer was acidified with aq. HCl and extracted with EtOAc (3×). The organic layer was washed with brine, dried (MgSO₄), and concentrated to yield 1-74 (9%) as an off-white solid: ¹H NMR ((CD₃)₂SO, 500 MHz) δ 13.05 (s, 1H), 8.73 (t, J=6.1 Hz, 1H), 3.36 (q, J=6.8 Hz, 2H), 1.58 (p, J=7.2 Hz, 2H), 1.33-1.20 (m, 10H), 0.85 (t, J=6.7 Hz, 3H); ¹³C NMR ((CD₃)₂SO, 125 MHz) δ 152.8, 152.7, 150.2, 144.4, 40.7, 31.2, 28.7, 28.6, 27.8, 26.4, 22.1, 13.9; HRMS (ES⁺) m/z calc'd. for C₁₂H₂₀N₅O₂ (M+H)⁺266.1612, found 266.1628.

Example 75. Synthesis of 6-(Phenethylamino)-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-ol (1-75)

Compound 1-75 was synthesized by procedure 1-A to yield 1-75 in 20% as a colorless solid: ¹H NMR ((CD₃)₂CO, 500 MHz) δ 11.80 (br s, 1H), 8.01 (s, 1H), 7.33-7.17 (m, 5H), 3.85-3.77 (m, 2H), 3.07-2.99 (m, 2H); ¹³C NMR ((CD₃)₂CO, 125 MHz) δ 153.6, 153.3, 150.9, 145.0, 140.0, 129.7, 129.3, 127.2, 43.4, 35.0; HRMS (ESI⁻) m/z calc'd. for C₁₂H₁₀N₅O₂ (M−H)⁻ 256.0840, found 256.0845.

Example 76. Synthesis of 6-((3,3,3-Trifluoropropyl)amino)-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-ol (1-76)

Compound 1-76 was synthesized by procedure 1-A to yield 1-76 in 66% as a light yellow solid: ¹H NMR ((CD₃)₂CO, 500 MHz) δ 11.82 (br s, 1H), 8.20 (s, 1H), 3.86 (q, J=6.7 Hz, 2H), 2.72 (qt, J=11.1, 7.0 Hz, 2H); ¹⁹F NMR ((CD₃)₂CO, 376 MHz) δ−65.98-−66.05 (m, 3 F); ¹³C NMR ((CD₃)₂CO, 125 MHz) δ153.8, 153.2, 150.7, 145.1, 127.6 (q, J_(CF)=276.1 Hz), 35.4 (q, J_(CF)=4.0 Hz), 32.7 (q, J_(CF)=27.8 Hz); HRMS (ESI⁻) m/z calc'd. for C₇H₅F₃N₅O₂ (M−H)⁻248.0401, found 248.0413.

Example 77. Synthesis of 6-((4-Bromobenzyl)amino)-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-ol (1-77)

A round-bottom flask containing 1-2 (0.200 g, 1.05 mmol) and K₂CO₃ (0.200 g, 1.45 mmol) in acetone/H₂O (9:1, 3 mL) was slowly diluted with a solution of (4-bromopheynl)methanamine (0.185 g, 0.994 mmol) in acetone/H₂O (9:1, 1 mL) and the resulting orange mixture was stirred at rt. After 1.5 h, the mixture was diluted with a solution of KOH in H₂O (0.320 g in 4 mL) and stirring was continued for an additional 30 min. The mixture was acidified with 1M HCl and extracted with EtOAc. The organic layer was washed with brine, dried (MgSO₄), and concentrated to a brown solid. The solid was purified by chromatography on SiO₂ (gradient: 0.5-2% MeOH/CH₂Cl₂) to yield 1-77 (44%) as a pale pink solid: ¹H NMR ((CD₃)₂CO, 500 MHz) δ 11.83 (br s, 1H), 8.55 (t, J=6.5 Hz, 1H), 7.50 (d, J=8.4 Hz, 2H), 7.41 (d, J=8.2 Hz, 2H), 4.77 (d, J=6.5 Hz, 2H); ¹³C NMR ((CD₃)₂CO, 125 MHz) δ 153.8, 153.4, 150.8, 145.2, 138.3, 132.2, 130.9, 121.5, 44.6; HRMS (ES⁺) m/z calc'd. for C₁₁H₉BrN₅O₂ (M+H)+321.9934, found 321.9940.

Example 78. Synthesis of 6-((4-Methylbenzyl)amino)-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-ol (1-78)

A round-bottom flask containing 1-2 (0.200 g, 1.05 mmol) and K₂CO₃ (0.200 g, 1.45 mmol) in acetone/H₂O (9:1, 3 mL) was slowly diluted with a solution of p-tolylmethanamine (0.120 g, 0.990 mmol) in acetone/H₂O (9:1, 1 mL) and the resulting dark mixture was stirred at rt. After 1.5 h, the mixture was diluted with a solution of KOH in H₂O (0.320 g in 4 mL) and stirring was continued for an additional 30 min. The mixture was acidified with 1M HCl and extracted with EtOAc. The organic layer was washed with brine, dried (MgSO₄), and concentrated to a brown residue. The residue was purified by chromatography on SiO₂ (0.7% MeOH/CH₂Cl₂) to yield 1-78 (29%) as an off-white solid: ¹H NMR ((CD₃)₂CO₃ 500 MHz) δ 11.76 (br s, 1H), 8.39 (s, 1H), 7.33 (d, J=7.7 Hz, 2H), 7.14 (d, J=7.7 Hz, 2H), 4.73 (d, J=6.4 Hz, 2H), 2.29 (s, 3H); ¹³C NMR ((CD₃)₂CO₃ 125 MHz) δ 153.6, 153.5, 150.9, 145.1, 137.7, 135.8, 129.9, 128.8, 45.0, 21.1; HRMS (ES⁺) m/z calc'd. for C₁₂H₁₂N₅O₂ (M+H)⁺258.0986, found 258.0993.

Example 79. Synthesis of 6-(Benzhydrylamino)-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-ol (1-79)

Compound 1-79 was synthesized by procedure 1-A to yield 1-79 in 63% as a colorless solid: ¹H NMR ((CD₃)₂CO₃ 400 MHz) δ 11.92 (br s, 1H), 8.30 (d, J=8.7 Hz, 1H), 7.48-7.45 (m, 4H), 7.399-7.35 (m, 4H), 7.33-7.28 (m, 2H), 6.58 (d, J=8.6 Hz, 1H); ¹³C NMR ((CD₃)₂CO₃ 100 MHz) δ 153.4, 152.9, 150.8, 145.2, 141.8, 129.5, 128.6, 128.4, 59.4; HRMS (ESI⁻) m/z calc'd. for C₁₇H₁₂N₅O₂ (M−H)⁻318.0996, found 318.1003.

Example 80. Synthesis of 6-((4-(Trifluoromethoxy)benzyl)amino)-[1,2,5]oxadiazolo[3,4-B]pyrazin-5-ol (1-80)

Synthesized by procedure 1-A to yield 1-80 in 36% as a colorless solid: ¹H NMR ((CD₃)₂CO₃ 500 MHz) δ 11.77 (br s, 1H), 8.59 (s, 1H), 7.59 (app d, J=8.6 Hz, 2H), 7.29 (d, J=8.2 Hz, 2H), 4.83 (d, J=6.5 Hz, 1H); ¹⁹F NMR ((CD₃)₂CO₃ 376 MHz) δ−58.65 (s, 3F); ¹³C NMR ((CD₃)₂CO₃ 125 MHz) δ153.9, 153.5, 150.9, 149.1 (q, J_(CF)=1.6 Hz), 145.2, 138.4, 130.6, 121.9, 121.4 (q, J_(CF)=255.2 Hz), 44.5; HRMS (ESI⁻) m/z calc'd. for C₁₂H₇F₃N₅O₃ (M−H)⁻326.0506, found 326.0492.

Example 81. Synthesis of 6-(((3S,5S,7S)-Adamantan-1-yl)amino)-[1,2,5]oxadiazolo[3,4-B]pyrazin-5-ol (1-81)

Compound 1-81 was synthesized by procedure 1-A at 75° C. to yield 1-81 in 55% as an off-white solid: ¹H NMR ((CD₃)₂CO, 500 MHz) δ 11.83 (br s, 1H), 6.97 (s, 1H), 2.30-2.24 (m, 6H), 2.16-2.12 (m, 3H), 1.80-1.72 (m, 6H); ¹³C NMR ((CD₃)₂CO, 125 MHz) δ 153.6, 152.0, 150.4, 144.7, 54.2, 41.0, 36.9, 30.3; HRMS (ESI⁻) m/z calc'd. for C₁₄H₁₆N₅O₂ (M−H)⁻286.1309, found 286.1311.

Example 82. Synthesis of 6-(((1R,3R,5S,7R)-3,5-Dimethyladamantan-1-yl)amino)-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-ol (1-82)

Compound 1-82 was synthesized by procedure 1-A at 75° C. to yield 1-82 in 38% as a yellow solid: ¹H NMR ((CD₃)₂CO, 500 MHz) δ 11.84 (br s, 1H), 6.98 (s, 1H), 2.22 (hept, J=3.2 Hz, 1H), 2.13-2.08 (m, 2H), 1.93-1.85 (m, 4H), 1.47 (dt, J=12.2, 2.7 Hz, 2H), 1.37 (dt, J=12.3, 2.8 Hz, 2H), 1.23 (qt, J=12.4, 2.1 Hz, 2H), 0.90 (s, 6H); ¹³C NMR ((CD₃)₂CO, 125 MHz) δ153.6, 152.0, 150.4, 144.7, 55.8, 51.1, 46.9, 43.2, 39.5, 31.0, 30.5; HRMS (ESI⁻) m/z calc'd. for C₁₆H₂₀N₅O₂ (M−H)⁻ 314.1622, found 314.1616.

Example 83. Synthesis of 6-((1-((1S,3S)-Adamantan-1-yl)ethyl)amino)-[1,2,5]oxadiazolo[3,4-B]pyrazin-5-ol (1-83)

Compound 1-83 was synthesized by procedure 1-A at 75° C. to yield 1-83 in 8% as a beige solid: ¹H NMR ((CD₃)₂CO, 500 MHz) δ 11.84 (s, 1H), 7.27 (d, J=9.7 Hz, 1H), 4.05 (dq, J=10.0, 6.9 Hz, 1H), 1.99 (p, J=3.2 Hz, 3H), 1.76-1.62 (m, 12H), 1.20 (d, J=6.9 Hz, 3H); ¹³C NMR ((CD₃)₂CO, 125 MHz) δ 153.6, 153.3, 151.0, 144.9, 55.9, 39.1, 37.7, 37.3, 29.3, 13.9; HRMS (ESI) m/z calc'd. for C₁₆H₂₀N₅O₂ (M−H)⁻314.1622, found 314.1618.

Example 84. Synthesis of 6-(((1R,3S,5R,7S)-3-Hydroxyadamantan-1-yl)amino)-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-ol (1-84)

Compound 1-84 was synthesized by procedure 1-A at 75° C. to yield 1-84 in 30% as an off-white solid: ¹H NMR ((CD₃)₂CO₃ 500 MHz) δ 11.84 (br s, 1H), 7.04 (s, 1H), 3.81 (br s, 1H), 2.31-2.28 (m, 2H), 2.22-2.11 (m, 6H), 1.77-1.68 (m, 4H), 1.67-1.57 (m, 2H); ¹³C NMR ((CD₃)₂CO₃ 125 MHz) δ 153.6, 152.0, 150.4, 144.7, 68.7, 56.6, 48.6, 45.0, 40.0, 35.7, 31.5; HRMS (ESI⁺) m/z calc'd. for C₁₄H₁₈N₅O₃ (M+H)⁺304.1404, found 304.1399.

Example 85. Synthesis of 6-(((1R,3R,5R,7R)-Adamantan-2-yl)amino)-[1,2,5]oxadiazolo[3,4-B]pyrazin-5-ol (1-85)

Compound 1-85 was synthesized by procedure 1-A with a reverse-phase HPLC purification using 0.1% TFA MeCN/H₂O solvent system to yield 1-85 in 5% as a colorless solid: ¹H NMR ((CD₃)₂CO₃ 500 MHz) δ 11.57 (br s, 1H), 7.38 (s, 1H), 4.27-4.24 (m, 1H), 2.18-2.16 (m, 2H), 2.00-1.88 (m, 8H), 1.83-1.81 (m, 2H), 1.74-1.70 (m, 2H); ¹³C NMR ((CD₃)₂CO₃ 125 MHz) δ153.9, 152.6, 151.0, 145.3, 56.2, 38.0, 37.6, 32.4, 31.9, 28.1; HRMS (ESI⁺) m/z calc'd. for C₁₄H₁₈N₅O₂ (M+H)+288.1455, found 288.1458.

Hydroxy Series with Alkoxy Aniline

Example 86. Synthesis of 6-((4-(Benzyloxy)phenyl)amino)-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-OL (1-86)

Compound 1-86 was synthesized by procedure 1-A at 75° C. to yield 1-86 in 30% as a yellow solid: ¹H NMR ((CD₃)₂CO₃ 500 MHz) δ 11.99 (br s, 1H), 9.45 (s, 1H), 8.05-8.02 (m, 2H), 7.52-7.50 (m, 2H), 7.42-7.39 (m, 2H), 7.35-7.32 (m, 1H), 7.13-7.09 (m, 2H), 5.17 (s, 2H); ¹³C NMR ((CD₃)₂CO, 125 MHz) δ 157.1, 153.7, 150.8, 150.6, 145.1, 138.3, 131.9, 129.3, 128.7, 128.5, 123.7, 115.8, 70.7; HRMS (ESI⁺) m/z calc'd. for C₁₇H₁₄N₅O₃ (M+H)⁺336.1091, found 336.1088.

Example 87. Synthesis of 6-(Benzo[D][1,3]dioxol-5-ylamino)-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-ol (1-87)

Compound 1-87 was synthesized by procedure 1-A to yield 1-87 in 60% as a yellow solid: ¹H NMR ((CD₃)₂CO, 500 MHz) δ 12.00 (br s, 1H), 9.44 (s, 1H), 7.77 (d, J=2.3 Hz, 1H), 7.56 (dd, J=8.5, 2.2 Hz, 1H), 6.91 (d, J=8.5 Hz, 1H), 6.05 (s, 2H); ¹³C NMR ((CD₃)₂CO, 125 MHz) δ153.6, 150.8, 150.5, 148.7, 145.8, 145.0, 132.9, 115.6, 108.8, 103.9, 102.5; HRMS (ESI⁻) m/z calc'd. for C₁₁H₆N₅O₄ (M−H)⁻272.0425, found 272.0430.

Example 88. Synthesis of 6-((4-(2,2,2-Trifluoroethoxy)phenyl)amino)-[1,2,5]oxadiazolo[3,4-B]pyrazin-5-ol (1-88) Step 1. Synthesis of 1-Nitro-4-(2,2,2-trifluoroethoxy)benzene (1-88-int)

In a sealed vial, a mixture of 1-fluoro-4-nitrobenzene (0.500 g, 3.54 mmol), potassium carbonate (1.25 g, 9.04 mmol), and 2,2,2-trifluoroethan-1-ol (0.50 mL, 6.9 mmol) in DMF (1 mL) was stirred at 80° C. for 24 h. The mixture was allowed to cool to rt and diluted with water. The yellow precipitate was filtered, rinsed with water, and dried to yield 1-88-int (94%) as a yellow crystalline solid: ¹H NMR ((CD₃)₂CO, 400 MHz) δ 8.31-8.27 (m, 2H), 7.33-7.29 (m, 2H), 4.90 (q, J=8.4 Hz, 2H).

Step 2. Synthesis of 6-((4-(2,2,2-Trifluoroethoxy)phenyl)amino)-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-ol (1-88)

In a round-bottom flask, a mixture of the 1-88-int and iron (325 mesh, 0.200 g, 3.58 mmol) in AcOH/MeOH (1:1, 4 mL) was stirred at 50° C. for 2 h. The mixture was filtered through Celite, rinsing with EtOAc, and concentrated to a dark oil. The oil was quenched with sat. aq. NaHCO₃, diluted with brine, and extracted with EtOAc. The organic layer was dried (Na₂SO₄) and concentrated to yield 4-(2,2,2-trifluoroethoxy)aniline as a crude dark oil (0.539 g).

Product 1-88 was synthesized using the crude aniline by procedure 1-A in 60% as a yellow solid: ¹H NMR ((CD₃)₂CO₃ 500 MHz) δ 12.00 (br s, 1H), 9.50 (s, 1H), 8.11-8.08 (m, 2H), 7.17-7.15 (m, 2H), 4.71 (q, J=8.6 Hz, 2H); ¹⁹F NMR ((CD₃)₂CO₃ 376 MHz) δ−74.73 (t, J=8.6 Hz, 3 F); ¹³C NMR ((CD₃)₂CO₃ 125 MHz) δ 155.6, 153.7, 151.0, 150.5, 145.1, 133.3, 124.9 (q, J_(CF)=289.2 Hz), 123.8, 116.1, 66.4 (q, J_(CF)=35.1 Hz); HRMS (ESI⁻) m/z calc'd. for C₁₂H₇F₃N₅O₃ (M−H)⁻326.0506, found 326.0508.

Example 89. Synthesis of Synthesis of 6-((3-Methyl-4-(2,2,2-trifluoroethoxy)phenyl)amino)-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-ol (1-89) Step 1. Synthesis of 2-Methyl-4-nitro-1-(2,2,2-trifluoroethoxy)benzene (1-89-int)

In a sealed vial, a mixture of 1-fluoro-2-methyl-4-nitrobenzene (0.500 g, 3.22 mmol), potassium carbonate (1.25 g, 9.04 mmol), and 2,2,2-trifluoroethan-1-ol (0.50 mL, 6.9 mmol) in DMF (1 mL) was stirred at 80° C. for 24 h. The mixture was allowed to cool to rt and diluted with a mixture of brine and water. The aqueous layer was extracted with EtOAc (2×). The combined organic layers were washed with brine, dried (Na₂SO₄), and concentrated to yield 1-89-int (79%) as a yellow crystalline solid: ¹H NMR ((CD₃)₂CO₃ 400 MHz) δ 8.16-8.15 (m, 1H), 8.14-8.12 (m, 1H), 7.30-7.27 (m, 1H), 4.90 (q, J=8.4 Hz, 2H), 2.35 (s, 3H).

Step 2. Synthesis of 6-((3-Methyl-4-(2,2,2-trifluoroethoxy)phenyl)amino)-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-ol (1-89)

In a round-bottom flask, a mixture of the 1-89-int and iron (325 mesh, 0.200 g, 3.58 mmol) in AcOH/MeOH (1:1, 4 mL) was stirred at 50° C. for 2 h. The mixture was filtered through Celite, rinsing with EtOAc, and concentrated to a dark oil. The oil was quenched with sat. aq. NaHCO₃, diluted with brine, and extracted with EtOAc. The organic layer was dried (Na₂SO₄) and concentrated to yield 3-methyl-4-(2,2,2-trifluoroethoxy)aniline as a crude dark oil (0.143 g). Product 1-89 was synthesized using the crude aniline by procedure 1-A in 66% as a yellow solid:¹H NMR ((CD₃)₂CO₃ 500 MHz) δ 11.98 (s, 1H), 9.40 (s, 1H), 8.00 (dd, J=8.9, 2.7 Hz, 1H), 7.88 (d, J=2.7 Hz, 1H), 7.12 (d, J=8.9 Hz, 1H), 4.70 (q, J=8.5 Hz, 2H), 2.28 (s, 3H); ¹⁹F NMR ((CD₃)₂CO₃ 376 MHz) δ-74.92 (t, J=8.5 Hz, 3 F); ¹³C NMR ((CD₃)₂CO₃ 125 MHz) δ 153.8, 153.7, 150.9, 150.5, 145.1, 133.0, 128.3, 125.0 (d, J_(CF)=277.3 Hz), 125.0, 121.0, 113.4, 66.7 (q, J_(CF)=34.8 Hz), 16.2; HRMS (ESI⁻) m/z calc'd. for C₁₃H₉F₃N₅O₃ (M−H)⁻340.0663, found 340.0667.

Example 90. Synthesis of 6-((3-Fluoro-4-(2,2,2-trifluoroethoxy)phenyl)amino)-[1,2,5]oxadiazolo[3,4-B ]pyrazin-5-ol (1-90) Step 1. Synthesis of 3-Fluoro-4-(2,2,2-trifluoroethoxy)aniline (1-90-int)

In a sealed vial, a mixture of 1,2-difluoro-4-nitrobenzene (0.300 g, 1.89 mmol), potassium carbonate (0.600 g, 4.34 mmol), and 2,2,2-trifluoroethan-1-ol (0.30 mL, 4.2 mmol) in DMF (2 mL) was stirred at 80° C. for 21 h. The mixture was allowed to cool to room temperature, diluted with water and brine, and extracted with EtOAc (2×). The combined organic layers were washed with brine (2×), dried (Na₂SO₄), and concentrated to yield 2-fluoro-4-nitro-1-(2,2,2-trifluoroethoxy)benzene (0.461 g) as a crude yellow oil.

In a vial, a mixture of the crude oil (0.461 g) and iron (325 mesh, 0.500 g, 8.95 mmol) in AcOH/MeOH (1:1, 5 mL) was stirred at 50° C. for 2 h under an atmosphere of N2. The mixture was quenched with sat. aq. NaHCO₃ and extracted with EtOAc (2×). The combined organic layers were washed with sat. aq. NaHCO₃ and then brine, dried (Na₂SO₄), and concentrated. The residue was purified by chromatography on SiO₂ (gradient: 15-40% EtOAc/hexanes) to yield 1-90-int (61%) as a clear yellow oil: ¹H NMR ((CD₃)₂CO, 400 MHz) δ 6.95 (dd, J=9.5, 8.7 Hz, 1H), 6.50 (dd, J=13.4, 2.6 Hz, 1H), 6.42 (ddd, J=8.7, 2.7, 1.3 Hz, 1H), 4.73 (br s, 2H), 4.49 (q, J=8.7 Hz, 2H); ¹⁹F NMR ((CD₃)₂CO, 376 MHz) δ−75.19 (t, J=8.6 Hz, 3F), −134.18 (dd, J=13.5, 9.6 Hz, 1F).

Step 2. 6-((3-Fluoro-4-(2,2,2-trifluoroethoxy)phenyl)amino)-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-ol (1-90)

Compound 1-90 was synthesized by procedure 1-B using 1-90-int to yield 1-90 in 53% as a yellow solid: ¹H NMR (400 MHz, Acetone-d₆) δ 9.62 (s, 1H), 8.18 (dd, J=13.5, 3.0 Hz, 1H), 7.94-7.86 (m, 1H), 7.37 (t, 1H), 4.79 (q, 2H); ¹⁹F NMR (376 MHz, Acetone-d₆) δ−74.94 (t, J=8.9 Hz, 3F), 132.89-−133.04 (m, 1F); ¹³C NMR (101 MHz, Acetone-d₆) δ Rotamers 153.48, 153.44*, 152.89 (d, J_(CF)=244.5 Hz), 151.19, 151.10*, 150.28, 145.12, 143.21 (dd, J_(CF)=11.1, 1.3 Hz), 134.18 (d, J_(CF)=9.6 Hz), 124.72 (q, J_(CF)=276.7 Hz), 118.37 (d, J_(CF)=3.8 Hz), 118.27 (d, J_(CF)=3.8 Hz)*, 117.70 (d, J_(CF)=2.7 Hz), 110.88 (d, J_(CF)=23.7 Hz), 110.79 (d, J_(CF)=23.8 Hz)*, 67.75 (q, J_(CF)=35.6 Hz). HRMS (ESI⁺) m/z calc'd. for C₁₂H₈F₄N₅O₃ (M+H)⁺346.0557, found 346.0574.

Example 91. Synthesis of 6-((4-(2,2,2-Trifluoroethoxy)-3-(trifluoromethyl)phenyl)amino)-[1,2,5]oxadiazolo[3,4-B ]pyrazin-5-ol (1-91) Step 1. Synthesis of 4-Nitro-1-(2,2,2-trifluoroethoxy)-2-(trifluoromethyl)benzene (1-91-int)

In a sealed vial, a mixture of 1-fluoro-4-nitro-2-(trifluoromethyl)benzene (0.500 g, 2.39 mmol), potassium carbonate (1.25 g, 9.04 mmol), and 2,2,2-trifluoroethan-1-ol (0.50 mL, 6.9 mmol) in DMF (1 mL) was stirred at 80° C. for 24 h. The mixture was allowed to cool to rt and diluted with a mixture of brine and water. The aqueous layer was extracted with EtOAc (2×). The combined organic layers were washed with brine, dried (Na₂SO₄), and concentrated to yield 1-91-int (87%, at 95% purity by NMR) as a yellow oil with some crystals forming: ¹H NMR ((CD₃)₂CO, 400 MHz) δ 8.59 (dd, J=9.3, 2.8 Hz, 1H), 8.51 (d, J=2.8 Hz, 1H), 7.67 (d, J=9.2 Hz, 1H), 5.10 (q, J=8.2 Hz, 2H); ¹⁹F NMR ((CD₃)₂CO, 376 MHz) δ−63.72 (s, 3F), −74.78 (t, J=8.5 Hz, 3F).

Step 2. 6-((4-(2,2,2-Trifluoroethoxy)-3-(trifluoromethyl)phenyl)amino)-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-ol (1-91)

In a round-bottom flask, a mixture of 1-91-int (0.200 g) and iron (325 mesh, 0.200 g, 3.58 mmol) in AcOH/MeOH (1:1, 4 mL) was stirred at 50° C. for 2 h. The mixture was filtered through Celite, rinsing with EtOAc, and concentrated to a dark oil. The oil was quenched with sat. aq. NaHCO₃, diluted with brine, and extracted with EtOAc. The organic layer was dried (Na₂SO₄) and concentrated to yield 4-(2,2,2-trifluoroethoxy)-3-(trifluoromethyl)aniline as a clear oil (0.152 g): ¹H NMR ((CD₃)₂CO, 400 MHz) δ 7.09 (d, J=8.8 Hz, 1H), 6.97-6.96 (m, 1H), 6.92-6.89 (m, 1H), 4.83 (br s, 2H), 4.60 (q, J=8.6 Hz, 2H); ¹⁹F NMR ((CD₃)₂CO, 376 MHz) δ−62.38 (s, 3F), −75.03 (t, J=8.6 Hz, 3F).

Product 1-91 was synthesized using the crude aniline by procedure 1-A in 46% as an orange solid: ¹H NMR ((CD₃)₂CO, 500 MHz) δ 12.03 (br s, 1H), 9.73 (s, 1H), 8.48 (d, J=2.8 Hz, 1H), 8.44 (dd, J=9.0, 2.8 Hz, 1H), 7.48 (d, J=8.9 Hz, 1H), 4.88 (q, J=8.4 Hz, 2H); ¹⁹F NMR ((CD₃)₂CO, 376 MHz) δ −62.78 (m, 3F), −74.84 (t, J=8.5 Hz, 3F); ¹³C NMR ((CD₃)₂CO, 125 MHz) b 153.5, 152.8, 151.4, 150.3, 145.2, 133.2, 127.6, 124.6 (q, J_(CF)=276.8 Hz), 124.2 (q, J_(CF)=271.5 Hz), 121.4 (q, J_(CF)=5.6 Hz), 119.8 (q, J_(CF)=31.4 Hz), 115.7, 67.0 (q, J_(CF)=35.7 Hz); HRMS (ESI⁻) m/z calc'd. for C₁₃H₆F₆N₅O₃ (M−H)⁻ 394.0380, found 394.0384.

Example 92. Synthesis of 6-((4-(Cyclopropylmethoxy)-3-(trifluoromethyl)phenyl)amino)-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-Ol) (1-92)

In a sealed vial, a mixture of 1-fluoro-4-nitro-2-(trifluoromethyl)benzene (0.250 g, 1.20 mmol), potassium carbonate (0.400 g, 2.89 mmol), and cyclopropylmethanol (0.25 mL, 3.1 mmol) in DMF (2 mL) was stirred at 80° C. for 22 h. The mixture was allowed to cool to rt, diluted with water and brine, and extracted with EtOAc (2×). The combined organic layers were washed with brine (2×), dried (Na₂SO₄), and concentrated to a crude oil. A mixture of the oil and iron (325 mesh, 0.300 g, 5.37 mmol) in AcOH/MeOH (1:1, 3 mL) was stirred at 50° C. for 2 h under an atmosphere of N2. The mixture was quenched with sat. aq. NaHCO₃ and extracted with EtOAc (2×). The combined organic layers were washed with sat. aq. NaHCO₃ (2×) and then brine, dried (Na₂SO₄), and concentrated to yield 4-(cyclopropylmethoxy)-3-(trifluoromethyl)aniline as a yellow oil (0.240 g). The oil was used crude in the next reaction. ¹H NMR ((CD₃)₂CO, 400 MHz) δ 6.95-6.92 (m, 2H), 6.87-6.83 (m, 1H), 4.59 (br s, 2H), 3.84 (d, J=6.5 Hz, 2H), 1.25-1.15 (m, 1H), 0.57-0.52 (m, 2H), 0.36-0.31 (m, 2H); ¹⁹F NMR ((CD₃)₂CO, 376 MHz) δ-62.20 (s, 3F).

Product 1-92 was synthesized using the crude aniline by procedure 1-A in 40% as a yellow solid: ¹H NMR ((CD₃)₂CO, 500 MHz) δ 12.02 (br s, 1H), 9.65 (s, 1H), 8.40 (d, J=2.8 Hz, 1H), 8.34 (dd, J=9.0, 2.8 Hz, 1H), 7.31 (d, J=9.0 Hz, 1H), 4.07 (d, J=6.6 Hz, 2H), 1.34-1.28 (m, 1H), 0.63-0.60 (m, 2H), 0.43-0.40 (m, 2H); ¹⁹F NMR ((CD₃)₂CO, 376 MHz) δ−62.71 (s, 3F); ¹³C NMR ((CD₃)₂CO, 125 MHz) δ 155.0 (q, J_(CF)=1.9 Hz), 153.5, 151.3, 150.4, 145.1, 131.4, 127.6, 124.6 (q, J_(CF)=271.9 Hz), 121.3 (q, J_(CF)=5.5 Hz), 119.2 (q, J_(CF)=30.7 Hz), 115.1, 74.1, 10.7, 3.3; HRMS (ES⁺) m/z calc'd. for C₁₅H₁₃F₃N₅O₃ (M+H)⁺368.0965, found 368.0966.

Example 93. Synthesis of 6-((2,2-Difluorobenzo[D][1,3]dioxol-5-yl)amino)-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-ol (1-93)

Compound 1-93 was synthesized by procedure 1-A to yield 1-93 in 59% as a yellow solid: ¹H NMR ((CD₃)₂CO, 500 MHz) δ 12.08 (br s, 1H), 9.71 (s, 1H), 8.23 (d, J=2.2 Hz, 1H), 7.91 (dd, J=8.8, 2.2 Hz, 1H), 7.38 (d, J=8.8 Hz, 1H); ¹⁹F NMR ((CD₃)₂CO, 376 MHz) δ−51.12 (s, 2F); ¹³C NMR ((CD₃)₂CO₃ 125 MHz) δ 153.5, 151.4, 150.2, 145.1, 144.2, 141.1, 135.3, 132.7 (t, J_(CF)=252.9 Hz), 118.1, 110.7, 104.8; HRMS (ES⁺) m/z calc'd. for C₁₁H₆F₂N₅O₄ (M+H)⁺310.0382, found 310.0386.

Example 94. Synthesis of 6-((2-Methoxyphenyl)amino)-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-ol (1-94)

Compound 1-94 was synthesized by procedure 1-B to yield 1-94 in 21% as a yellow solid: ¹H NMR (400 MHz, Acetone-d₆) δ 12.18 (s, 1H), 9.53 (s, 1H), 8.80 (dd, J=8.1, 1.6 Hz, 1H), 7.25-7.12 (m, 2H), 7.14-7.05 (m, 1H), 4.03 (s, 3H); HRMS (ESI⁻) m/z calc'd. for C₁₁H₈N₅O₃ (M−H)⁻ 258.0632, found 258.0642.

Example 95. Synthesis of 6-((4-Butoxyphenyl)amino)-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-ol (1-95)

Compound 1-95 was synthesized by procedure 1-B to yield 1-95 in 75% as tan solid: ¹H NMR (400 MHz, Acetone-d₆) δ 11.97 (s, 1H), 9.40 (s, 1H), 8.16-7.87 (m, 2H), 7.08-6.89 (m, 2H), 4.02 (t, J=6.5 Hz, 2H), 1.87-1.69 (m, 2H), 1.63-1.42 (m, 2H), 0.97 (t, J=7.4 Hz, 3H); ¹³C NMR (101 MHz, Acetone-d₆) δ 156.61, 152.78, 149.74, 149.66, 144.09, 130.63, 122.71, 114.44, 67.56, 31.18, 18.99, 13.23; HRMS (ESI⁺) m/z Calc'd. for C₁₄H₁₆N₅O₃ (M+H)⁺302.1247, found 302.1253.

Example 96. Synthesis of 6-((3-Butoxyphenyl)amino)-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-ol (1-96)

In a vial, 1-iodobutane (0.20 mL, 1.8 mmol) was added to a stirring mixture of N-(3-hydroxyphenyl)acetamide (0.150 g, 0.992 mmol) and K₂CO₃ (0.200 g, 1.45 mmol) in acetone (1.5 mL). The resulting mixture was stirred for 2 d. Additional 1-iodobutane (0.20 mL, 1.8 mmol) was added and the mixture was heated to 40° C. for 9 h. The mixture was diluted with EtOAc, washed with brine, dried (Na₂SO₄), and concentrated to a clear oil (0.177 g). The oil was heated in a mixture of 6M aq HCl (5 mL) and dioxane (3 mL) at 90° C. for 6 h. The mixture was allowed to cool to rt, basified with 1M NaOH, and extracted with EtOAc (2×). The combined organic layers were washed with brine, dried (Na₂SO₄), and concentrated to yield 3-butoxyaniline as a crude orange oil (0.123 g).

Product 1-96 was synthesized using the crude aniline by procedure 1-A in 37% as an off-white solid: ¹H NMR ((CD₃)₂CO₃ 400 MHz) δ12.04 (br s, 1H), 9.42 (s, 1H), 7.83 (t, J=2.2 Hz, 1H), 7.68 (ddd, J=8.2, 2.1, 0.9 Hz), 7.33 (t, J=8.2 Hz, 1H), 6.79 (ddd, J=8.2, 2.5, 0.9 Hz, 1H), 4.04 (t, J=6.5 Hz, 2H), 1.82-1.75 (m, 2H), 1.56-1.47 (m, 2H), 0.98 (t, J=7.4 Hz, 3H); ¹³C NMR ((CD₃)₂CO₃ 125 MHz) δ 160.5, 153.6, 151.0, 150.4, 145.0, 139.7, 130.5, 114.1, 111.9, 108.4, 68.4, 32.0, 19.9, 14.1; HRMS (ES⁺) m/z calc'd. for C₁₄H₁₆N₅O₃ (M+H)⁺302.1248, found 302.1251.

Example 97. Synthesis of 6-((3-((4-(Trifluoromethyl)benzyl)oxy)phenyl)amino)-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-ol (1-97) Step 1. Synthesis of 3-((4-(Trifluoromethyl)benzyl)oxy)aniline (1-97-int)

In a vial, 1-(bromomethyl)-4-(trifluoromethyl)benzene (0.350 g, 1.46 mmol) was added to a stirring mixture of N-(3-hydroxyphenyl)acetamide (0.150 g, 0.992 mmol) and K₂CO₃ (0.200 g, 1.45 mmol) in acetone (1.5 mL). The resulting mixture was stirred for 2 d. The mixture was diluted in EtOAc, washed with brine, dried (Na₂SO₄), and concentrated to a colorless solid. The solid was triturated with hexanes, filtered, rinsed with hexanes, and collected to yield N-(3-((4-(trifluoromethyl)benzyl) oxy)phenyl)acetamide (0.291 g) as a colorless solid: ¹H NMR ((CD₃)₂CO₃ 400 MHz) δ 9.14 (br s, 1H), 7.80-7.66 (m, 4H), 7.56 (t, J=2.3 Hz, 1H), 7.19 (t, J=8.1 Hz, 1H), 7.12 (ddd, J=8.1, 1.9, 1.0 Hz, 1H), 6.72 (ddd, J=8.1 Hz, 2.5, 1.0 Hz, 1H), 5.22 (s, 2H), 2.06 (s, 3H); ¹⁹F NMR ((CD₃)₂CO₃ 376 MHz) δ 62.99 (s, 3F).

The solid was heated in a mixture of 6M aq. HCl (5 mL) and dioxane (3 mL) at 90° C. for 6 h. The mixture was allowed to cool to rt, basified with 1 M NaOH, and extracted with EtOAc (2×). The combined organic layers were washed with brine, dried (Na₂SO₄), and concentrated to yield 1-97-int (49%) as a colorless solid: ¹H NMR ((CD₃)₂CO₃ 400 MHz) δ 7.75-7.66 (m, 4H), 6.95 (t, J=8.1 Hz, 1H), 6.35 (t, J=2.2 Hz, 1H), 6.30-6.24 (m, 2H), 5.15 (s, 2H), 4.64 (br s, 2H); ¹⁹F NMR ((CD₃)₂CO₃ 376 MHz) δ-62.96 (s, 3F).

Step 2. Synthesis of 6-((3-((4-(Trifluoromethyl)benzyl)oxy)phenyl)amino)-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-ol (1-97)

Compound 1-97 was synthesized by procedure 1-A to yield 1-97 in 60% as an off-white solid: ¹H NMR ((CD₃)₂CO₃ 500 MHz) δ 12.06 (br s, 1H), 9.45 (s, 1H), 7.98 (t, J=2.3 Hz, 1H), 7.76 (app s, 4H), 7.70 (dd, J=8.2, 2.0 Hz, 1H), 7.36 (t, J=8.2 Hz, 1H), 6.90 (dd, J=8.3, 2.4 Hz, 1H), 5.29 (s, 2H); ¹⁹F NMR ((CD₃)₂CO₃ 376 MHz) δ−62.9 (s, 3F); ¹³C NMR ((CD₃)₂CO₃ 125 MHz) δ159.8, 153.5, 151.1, 150.3, 145.0, 142.9, 139.8, 130.6, 130.2 (q, J_(CF)=32.1 Hz), 128.9, 126.2 (q, J_(CF)=3.9 Hz), 125.3 (q, J_(CF)=271.3 Hz), 114.7, 112.3, 108.7, 69.7; HRMS (ES⁺) m/z calc'd. for C₁₈H₁₃F₃N₅O₃ (M+H)⁺404.0965, found 404.0961.

Example 98. Synthesis of 2-(3-((6-Hydroxy-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-yl)amino)phenoxy)-1-(4-(trifluoromethoxy)phenyl)ethan-1-One (1-98)

In a vial, 2-bromo-1-(4-(trifluoromethoxy)phenyl)ethan-1-one (0.300 g, 1.06 mmol) was added to a stirring mixture of N-(3-hydroxyphenyl)acetamide (0.150 g, 0.992 mmol) and K₂CO₃ (0.200 g, 1.45 mmol) in acetone (3 mL). The resulting mixture was stirred for 2 d. Additional alkyl halide (0.050 g) was added and the mixture was heated to 40° C. for 9 h. The mixture was diluted with EtOAc, washed with brine, dried (Na₂SO₄), and concentrated to an orange oil (0.436 g).

The crude oil was heated in a mixture of 6 M aq. HCl (5 mL) and dioxane (3 mL) at 90° C. for 6 h. The mixture was allowed to cool to rt, basified with 1 M NaOH, and extracted with EtOAc (2×). The combined organic layers were washed with brine, dried (Na₂SO₄), and concentrated to yield 2-(3-aminophenoxy)-1-(4-(trifluoromethoxy)phenyl)ethan-1-one as a crude orange residue (0.400 g).

Product 1-98 was synthesized using the crude aniline by procedure 1-A in 32% as a brown solid: ¹H NMR ((CD₃)₂CO₃ 500 MHz) δ 12.04 (br s, 1H), 9.43 (s, 1H), 8.24-8.21 (m, 2H), 7.86 (t, J=2.3 Hz, 1H), 7.77 (dd, J=8.1, 2.0 Hz, 1H), 7.53-7.51 (m, 2H), 7.35 (t, J=8.2 Hz, 1H), 6.87 (dd, J=8.3, 2.5 Hz, 1H), 5.58 (s, 2H); ¹⁹F NMR ((CD₃)₂CO₃ 376 MHz) δ−58.38 (s, 3F); ¹³C NMR ((CD₃)₂CO₃ 125 MHz) δ193.7, 159.6, 153.5, 153.4 (q, J_(CF)=1.9 Hz), 151.1, 150.3, 145.0, 139.8, 134.5, 131.3, 130.6, 121.7, 121.3 (q, J_(CF)=257.1 Hz), 114.8, 112.0, 108.6, 71.3; HRMS (ES⁺) m/z calc'd. for C₁₉H₁₃F₃N₅O₅ (M+H)⁺448.0863, found 448.0875.

Example 99. Synthesis of 6-((3-Fluoro-4-(4,4,4-trifluorobutoxy)phenyl)amino)-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-ol (1-99)

In a sealed microwave vial, a mixture of 1,2-difluoro-4-nitrobenzene (0.350 g, 2.20 mmol), 4,4,4-trifluorobutan-1-ol (0.35 mL, 3.3 mmol), and K₂CO₃ (0.700 g, 5.07 mmol) in DMF (2 mL) was stirred at 80° C. for 22 h. The mixture was allowed to cool to rt, diluted with water and brine, and extracted with EtOAc (2×). The combined organic layers were dried (Na₂SO₄) and concentrated to a crude yellow liquid (0.657 g). In a 6-dram vial, a mixture of the liquid (0.657 g) and iron (325 mesh, 0.650 g, 11.6 mmol) in AcOH/MeOH (1:1, 5 mL) was stirred at 50° C. for 2 h under an atmosphere of N₂. The mixture was filtered through Celite (EtOAc), quenched with sat. aq. NaHCO₃, and extracted with EtOAc (2×). The combined organic layers were dried (Na₂SO₄) and concentrated. The residue was purified by chromatography on SiO₂ (gradient: 20-30% EtOAc/hexanes) to yield 3-fluoro-4-(4,4,4-trifluorobutoxy)aniline (0.421 g) as a crude orange liquid. ¹H NMR ((CD₃)₂CO₃ 400 MHz) δ 6.86 (dd, J=9.5, 8.7 Hz, 1H), 6.48 (dd, J=13.4, 2.6 Hz, 1H) 6.39 (ddd, J=8.7, 2.7, 1.3 Hz, 1H), 4.57 (s, 2H), 4.01 (t, J=6.1 Hz, 2H), 2.49-2.36 (m, 2H), 2.00-1.93 (m, 2H); ¹⁹F NMR ((CD₃)₂CO₃ 376 MHz) δ-67.05 (t, J=11.2 Hz, 3F), −134.85-−134.91 (m, 1F).

Product 1-99 was synthesized using the crude aniline by procedure 1-A in 60% as a yellow solid: ¹H NMR ((CD₃)₂SO, 500 MHz) δ 13.28 (br s, 1H), 10.34 (s, 1H), 8.01 (dd, J=13.7, 2.6 Hz, 1H), 7.85 (ddd, J=9.0, 2.5, 1.3 Hz, 1H), 7.23 (t, J=9.3 Hz, 1H), 4.13 (t, J=6.2 Hz, 2H), 2.51-2.38 (m, 2H), 1.99-1.93 (m, 2H); ¹⁹F NMR ((CD₃)₂CO₃ 376 MHz) δ−67.01 (t, J=11.3 Hz, 3F), −133.97-134.035 (m, 1F); ¹³C NMR ((CD₃)₂SO, 125 MHz) δ 152.97, 150.87 (d, J_(CF)=242.1 Hz), 150.55, 149.60, 144.51, 142.98 (d, J_(CF)=10.8 Hz), 131.53 (d, J_(CF)=9.6 Hz), 127.61 (q, J_(CF)=276.1 Hz), 117.96 (d, J_(CF)=3.4 Hz), 115.20 (d, J_(CF)=2.5 Hz), 109.98 (d, J_(CF)=23.1 Hz), 67.35, 29.43 (q, J_(CF)=28.0 Hz), 21.64 (q, J_(CF)=3.1 Hz); HRMS (ES⁻) m/z calc'd. for C₁₄H₁₀F₄N₅O₃ (M−H)⁻ 372.0725, found 372.0726.

Example 100. Synthesis of 6-((4-(4,4,4-Trifluorobutoxy)-3-(trifluoromethyl)phenyl)amino)-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-ol (1-100)

In a sealed microwave vial, a mixture of 1-fluoro-4-nitro-2-(trifluoromethyl)benzene (0.400 g, 1.91 mmol), 4,4,4-trifluorobutan-1-ol (0.35 mL, 3.3 mmol), and K₂CO₃ (0.700 g, 5.07 mmol) in DMF (2 mL) was stirred at 80° C. for 22 h. The mixture was allowed to cool to rt, diluted with water and brine, and extracted with EtOAc (2×). The combined organic layers were dried (Na₂SO₄) and concentrated to a crude orange liquid (0.913 g). In a 6-dram vial, a mixture of the liquid (0.913 g) and iron (325 mesh, 0.650 g, 11.6 mmol) in AcOH/MeOH (1:1, 5 mL) was stirred at 50° C. for 2 h under an atmosphere of N2. The mixture was filtered through Celite (EtOAc), quenched with sat. aq. NaHCO₃, and extracted with EtOAc (2×). The combined organic layers were dried (Na₂SO₄) and concentrated. The residue was purified by chromatography on SiO₂ (gradient: 20-30% EtOAc/hexanes) to yield 4-(4,4,4-trifluorobutoxy)-3-(trifluoromethyl)aniline (0.452 g) as a crude orange liquid that solidified to an offwhite solid: ¹H NMR ((CD₃)₂CO, 400 MHz) δ 6.99-6.96 (m, 1H), 6.95-6.94 (m, 1H), 6.90-6.86 (m, 1H), 4.65 (br s, 2H), 4.10-4.07 (m, 2H), 2.49-2.36 (m, 2H), 2.04-1.98 (m, 2H); ¹⁹F NMR ((CD₃)₂CO, 376 MHz) δ−62.81 (d, J=4.0 Hz, 3F), −67.13 (dt, J=11.0, 3.5 Hz, 3F).

Product 1-100 was synthesized using the crude aniline by procedure 1-A in 53% as a yellow solid: ¹H NMR ((CD₃)₂SO, 500 MHz) δ 13.28 (br s, 1H), 10.45 (s, 1H), 8.37 (d, J=2.6 Hz, 1H), 8.28 (dd, J=9.1, 2.7 Hz, 1H), 7.34 (d, J=9.1 Hz, 1H), 4.20 (t, J=6.0 Hz, 2H), 2.47-2.37 (m, 2H), 2.00-1.94 (m, 2H); ¹⁹F NMR ((CD₃)₂CO, 376 MHz) δ−62.81 (s, 3F), −67.09 (t, J_(HF)=11.5 Hz, 3F); ¹³C NMR ((CD₃)₂S0, 125 MHz) δ 153.0, 152.8, 150.8, 149.6, 144.6, 130.8, 127.6 (q, J_(CF)=276.0 Hz), 127.4, 123.5 (q, J_(CF)=272.1 Hz), 120.5 (q, J_(CF)=5.9 Hz), 116.8 (q, J_(CF)=30.4 Hz), 114.0, 66.8, 29.3 (q, J_(CF)=28.3 Hz), 21.6 (q, J_(CF)=3.2 Hz); HRMS (ES⁻) m/z calc'd. for C₁₅H₁₀F₆N₅O₃ (M−H)⁻ 422.0693, found 422.0696.

Hydroxy Series with Biphenyl Anilines

Example 101. Synthesis of 6-((4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)amino)-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-ol (1-101)

Compound 1-101 was synthesized by procedure 1-A to yield 1-101 in 59% as a yellow solid: ¹H NMR ((CD₃)₂CO, 500 MHz) δ 12.07 (br s, 1H), 9.54 (s, 1H), 8.16-8.14 (m, 2H), 7.83-7.81 (m, 2H), 1.35 (s, 12H). ¹³C NMR ((CD₃)₂CO, 125 MHz) δ 153.6, 151.2, 150.3, 145.1, 141.2, 136.3, 121.0, 84.6, 25.2; HRMS (ES⁺) m/z calc'd. for C₁₆H₁₉BN₅O₄ (M+H)⁺356.1525, found 356.1540.

Example 102. Synthesis of 6-((3-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)amino)-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-ol (1-102)

Compound 1-102 was synthesized by procedure 1-A to yield 1-102 in 45% as a light yellow solid: ¹H NMR ((CD₃)₂CO, 400 MHz) δ 11.96 (br s, 1H), 9.55 (s, 1H), 8.31-8.29 (m, 1H), 8.28-8.24 (m, 1H), 7.60 (dt, J=7.3, 1.1 Hz, 1H), 7.50-7.46 (m, 1H), 1.36 (s, 12H).

Example 103. Synthesis of 6-([1,1′-Biphenyl]-4-ylamino)-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-ol (1-103)

Compound 1-103 was synthesized by procedure 1-A in acetone to yield 1-103 in 53% as a burnt-orange solid: ¹H NMR ((CD₃)₂CO, 500 MHz) δ12.01 (br s, 1H), 9.60 (s, 1H), 8.25-8.23 (m, 2H), 7.80-7.75 (m, 2H), 7.74-7.69 (m, 2H), 7.49-7.46 (m, 2H), 7.39-7.33 (m, 1H); ¹³C NMR ((CD₃)₂CO, 125 MHz) δ 153.66, 151.15, 150.48, 145.15, 141.07, 138.40, 138.07, 129.79, 128.19, 128.10, 127.54, 122.50; HRMS (ESI⁻) m/z calc'd. for C₁₆H₁₀N₅O₂ (M−H)⁻304.0840, found 304.0850.

Example 104. Synthesis of 6-([1,1′-Biphenyl]-3-ylamino)-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-ol (1-104)

Compound 1-104 was synthesized by procedure 1-F using 1-18 to yield 1-104 in 47% as a yellow solid: ¹H NMR (400 MHz, Acetone-d₆) δ 12.04 (s, 1H), 9.60 (s, 1H), 8.40 (t, J=1.8 Hz, 1H), 8.23-8.18 (m, 1H), 7.74-7.69 (m, 2H), 7.59-7.47 (m, 4H), 7.40 (tt, J=7.5, 1.2 Hz, 1H); ¹³C NMR (101 MHz, Acetone-d₆) δ 153.72, 151.37, 150.51, 145.19, 142.69, 141.41, 139.31, 130.40, 129.90, 128.63, 127.87, 124.44, 121.05, 120.75; HRMS (ESI⁻) m/z calc'd. for C₁₆H₁₀N₅O₂ (M−H)⁻304.0840, found 304.0872.

Example 105. Synthesis of 6-((4′-(Trifluoromethoxy)-[1,1′-biphenyl]-4-yl)amino)-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-ol (1-105)

Compound 1-105 was synthesized by procedure 1-E using 1-101 to yield 1-105 in 57% as a yellow solid: ¹H NMR ((CD₃)₂CO, 400 MHz) δ 12.08 (br s, 1H), 9.63 (s, 1H), 8.28-8.25 (m, 2H), 7.87-7.83 (m, 2H), 7.82-7.78 (m, 2H), 7.46-7.43 (m, 2H); ¹⁹F NMR ((CD₃)₂CO, 376 MHz) δ-58.57 (s, 3F); ¹³C NMR ((CD₃)₂CO, 125 MHz) δ 153.6, 151.2, 150.4, 149.3 (q, J_(CF)=2.2 Hz), 145.1, 140.3, 138.5, 136.8, 129.3, 128.2, 122.5, 122.3, 121.5 (q, J_(CF)=255.3 Hz); HRMS (ES⁺) m/z calc'd. for C₁₇H₁₁F₃N₅O₃ (M+H)⁺390.0809, found 390.0821.

Example 106. Synthesis of 6-((4-(Thiophen-2-yl)phenyl)amino)-[1,2,5]oxadiazolo[3,4-B]pyrazin-5-ol (1-106)

Compound 1-106 was synthesized by procedure 1-E using 1-101 to yield 1-106 in 66% as a yellow solid: ¹H NMR ((CD₃)₂CO₃ 400 MHz) δ 12.07 (br s, 1H), 9.61 (s, 1H), 8.21-8.19 (m, 2H), 7.78-7.76 (m, 2H), 7.49 (dd, J=3.6, 1.2 Hz, 1H), 7.46 (dd, J=5.1, 1.1 Hz, 1H), 7.14 (dd, J=5.1, 3.6 Hz, 1H); ¹³C NMR ((CD₃)₂CO₃ 125 MHz) δ 153.6, 151.1, 150.4, 145.2, 144.3, 138.0, 132.0, 129.2, 126.9, 125.9, 124.2, 122.5; HRMS (ES⁺) m/z calc'd. for C₁₄H₁₀N₅O₂S (M+H)⁺312.0550, found 312.0566.

Example 107. Synthesis of 6-((4-(6-(Trifluoromethyl)pyridin-3-yl)phenyl)amino)-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-ol (1-107)

Compound 1-107 was synthesized by procedure 1-E using 1-101 to yield 1-107 in 71% as a yellow solid: ¹H NMR ((CD₃)₂CO₃ 500 MHz) δ 12.05 (br s, 1H), 9.70 (s, 1H), 9.11 (d, J=2.2 Hz, 1H), 8.38 (dd, J=8.3, 2.3 Hz, 1H), 8.36-8.33 (m, 2H), 7.96-7.92 (m, 3H); ¹⁹F NMR ((CD₃)₂CO₃ 376 MHz) δ−68.19 (s, 3F); ¹³C NMR ((CD₃)₂CO₃ 125 MHz) δ 153.6, 151.4, 150.4, 149.1, 146.9 (q, J_(CF)=34.3 Hz), 145.2, 139.6, 136.4, 133.4, 128.8, 123.0 (q, J_(CF)=272.9 Hz), 122.8, 121.5 (q, J_(CF)=2.6 Hz); HRMS (ES⁺) m/z calc'd. for C₁₆H₁₀F₃N₆O₂ (M+H)⁺375.0812, found 375.0821.

Example 108. Synthesis of 6-((4′-(Difluoromethoxy)-[1,1′-biphenyl]-4-yl)amino)-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-ol (1-108)

Compound 1-108 was synthesized by procedure 1-E using 1-101 to yield 1-108 in 65% as a yellow solid: ¹H NMR ((CD₃)₂CO₃ 500 MHz) δ 12.02 (br s, 1H), 9.61 (s, 1H), 8.26-8.22 (m, 2H), 7.80-7.74 (m, 4H), 7.32-7.27 (m, 2H), 7.05 (t, J_(HF)=74.3 Hz, 1H); ¹⁹F NMR ((CD₃)₂CO₃ 376 MHz) δ 82.70 (d, J_(HF)=74.3, 2F); ¹³C NMR ((CD₃)₂CO₃ 125 MHz) δ153.7, 151.9 (t, J_(CF)=3.1 Hz), 151.1, 150.4, 145.2, 138.22, 138.16, 137.2, 129.1, 128.0, 122.5, 120.3, 117.5 (t, J_(CF)=257.2 Hz); HRMS (ES⁺) m/z calc'd. for C₁₇H₁₂F₂N₅O₃ (M+H)⁺372.0903, found 372.0902.

Example 109. Synthesis of 6-((3′-(Difluoromethyl)-4′-fluoro-[1,1′-biphenyl]-4-yl)amino)-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-ol (1-109)

Compound 1-109 was synthesized by procedure 1-E using 1-101 to yield 1-109 in 32% as a yellow solid: ¹H NMR ((CD₃)₂CO₃ 500 MHz) δ 12.08 (br s, 1H), 9.63 (s, 1H), 8.28-8.25 (m, 2H), 7.96-7.92 (m, 2H), 7.82-7.79 (m, 2H), 7.43-7.39 (m, 2H), 7.43-7.39 (m, 1H), 7.16 (t, J_(HF)=54.6 Hz, 1H); ¹⁹F NMR ((CD₃)₂CO₃ 376 MHz) δ−114.52-−114.68 (m, 2F), −122.90-−122.98 (m, 1F); ¹³C NMR ((CD₃)₂CO₃ 125 MHz) δ 160.7 (dt, J_(CF)=251.1, 5.1 Hz), 153.6, 151.2, 150.4, 145.1, 138.5, 138.0 (dt, J_(CF)=3.8 Hz), 136.3, 132.1 (dt, J_(CF)=8.5, 1.9 Hz), 128.2, 126.2 (dt, J_(CF)=6.2, 3.0 Hz), 123.1 (dt, J_(CF)=23.1, 12.8 Hz), 122.6, 117.6 (d, J_(CF)=20.8 Hz), 112.8 (dt, J_(CF)=236.1, 4.3 Hz); HRMS (ES⁺) m/z calc'd. for C₁₇H₁₁F₃N₅O₂ (M+H)⁺374.0859, found 374.0860.

Example 110. Synthesis of 6-((3′-(Trifluoromethyl)-[1,1′-biphenyl]-4-yl)amino)-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-ol (1-110)

Compound 1-110 was synthesized by procedure 1-E using 1-101 to yield 1-110 in 44% as a yellow solid: ¹H NMR ((CD₃)₂CO₃ 500 MHz) δ 12.08 (br s, 1H), 9.65 (s, 1H), 8.30-8.27 (m, 2H), 8.02-8.01 (m, 2H), 7.87-7.84 (m, 2H), 7.73-7.71 (m, 2H); ¹⁹F NMR ((CD₃)₂CO₃ 376 MHz) δ-63.09 (s, 3F); ¹³C NMR ((CD₃)₂CO₃ 125 MHz) δ 153.6, 151.2, 150.4, 145.1, 142.1, 138.8, 136.6, 131.6 (q, J_(CF)=31.9 Hz), 131.4, 130.8, 128.4, 125.4 (q, J_(CF)=271.7 Hz), 124.7 (q, J_(CF)=4.0 Hz), 124.1 (q, J_(CF)=3.9 Hz), 122.6; HRMS (ES⁺) m/z calc'd. for C₁₇H₁₁F₃N₅O₂ (M+H)⁺374.0859, found 374.0859.

Example 111. Synthesis of 6-((3′-(Trifluoromethoxy)-[1,1′-biphenyl]-4-yl)amino)-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-ol (1-111)

Compound 1-111 was synthesized by procedure 1-E using 1-101 to yield 1-111 in 43% as a yellow solid: ¹H NMR ((CD₃)₂CO, 500 MHz) δ 12.09 (br s, 1H), 9.64 (s, 1H), 8.29-8.26 (m, 2H), 7.83-7.81 (m, 2H), 7.77-7.75 (m, 1H), 7.66-7.64 (m, 1H), 7.62 (t, J=8.0 Hz, 1H), 7.35-7.32 (m, 1H); ¹⁹F NMR ((CD₃)₂CO, 376 MHz) δ-58.43 (s, 3F); ¹³C NMR ((CD₃)₂CO, 125 MHz) δ153.6, 151.2, 150.5 (q, J_(CF)=1.9 Hz), 150.4, 145.1, 143.4, 138.8, 136.5, 131.6, 128.3, 126.4, 122.6, 121.5 (q, J_(CF)=255.5 Hz), 120.5, 120.1; HRMS (ES⁺) m/z calc'd. for C₁₇H₁₁F₃N₅O₃ (M+H)⁺390.0809, found 390.0811.

Example 112. Synthesis of 6-((4′-Fluoro-[1,1′-biphenyl]-4-yl)amino)-[1,2,5]oxadiazolo[3,4-B]pyrazin-5-ol (1-112)

Compound 1-112 was synthesized by procedure 1-A using acetone to yield 1-112 in 60% as a yellow solid: ¹H NMR ((CD₃)₂CO, 500 MHz) δ 12.04 (br s, 1H), 9.58 (s, 1H), 8.24-8.21 (m, 2H), 7.76-7.73 (m, 4H), 7.25-7.22 (m, 2H); ¹⁹F NMR ((CD₃)₂CO, 376 MHz) δ−117.30-−117.38 (m, F); 13C NMR ((CD₃)₂CO, 125 MHz) δ 163.3 (d, J_(CF)=244.6 Hz), 153.6, 151.1, 150.4, 145.1, 138.1, 137.5 (d, J_(CF)=3.3 Hz), 137.3, 129.4 (d, J_(CF)=8.2 Hz), 128.0, 122.5, 116.5 (d, J_(CF)=21.7 Hz); HRMS (ES⁺) m/z calc'd. for C₁₆H11FN₅O₂ (M+H)⁺324.0891, found 324.0895.

Example 113. Synthesis of 6-((4′-(Difluoromethoxy)-[1,1′-biphenyl]-3-yl)amino)-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-ol (1-113)

Compound 1-113 was synthesized by procedure 1-E using 1-102 to yield 1-113 in 43% as an off-white solid: ¹H NMR ((CD₃)₂CO, 500 MHz) δ 12.06 (br s, 1H), 9.61 (s, 1H), 8.40 (t, J=2.0 Hz, 1H), 8.23-8.20 (m, 1H), 7.79-7.76 (m, 2H), 7.56 (t, J=7.8 Hz, 1H), 7.52 (dt, J=7.8, 1.5 Hz, 1H), 7.33-7.30 (m, 2H), 7.07 (t, J_(HF)=74.2 Hz, 1H); ¹⁹F NMR ((CD₃)₂CO, 376 MHz) δ−82.74 (d, J_(HF)=74.2 Hz, 2F); ¹³C NMR ((CD₃)₂CO, 125 MHz) δ 153.7, 152.2 (t, J_(CF)=3.1 Hz), 151.3, 150.4, 145.1, 141.5, 139.3, 138.5, 130.4, 129.4, 124.3, 121.1, 120.6, 120.3, 117.5 (t, J_(CF)=257.2 Hz); HRMS (ES⁺) m/z calc'd. for C₁₇H₁₂F₂N₅O₃ (M+H)⁺372.0903, found 372.0915.

Example 114. Synthesis of 6-((3′-(Difluoromethyl)-4′-fluoro-[1,1′-biphenyl]-3-yl)amino)-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-ol (1-114)

Compound 1-114 was synthesized by procedure 1-E using 1-102 to yield 1-114 in 34% as a yellow solid: ¹H NMR ((CD₃)₂CO, 500 MHz) δ 12.09 (br s, 1H), 9.64 (s, 1H), 8.39-8.38 (m, 1H), 8.30-8.27 (m, 1H), 7.96-7.92 (m, 2H), 7.61-7.54 (m, 2H), 7.44 (t, J=9.3 Hz, 1H), 7.18 (t, J_(HF)=54.6 Hz, 1H); ¹⁹F NMR ((CD₃)₂CO, 376 MHz) δ−114.84 (dd, J_(HF)=54.6 Hz, J_(FF)=4.0 Hz, 2F), −122.43-−122.51 (m, 1F); ¹³C NMR ((CD₃)₂CO, 125 MHz) δ 160.9 (dt, J_(CF)=251.6, 5.3 Hz), 153.6, 151.3, 150.4, 145.1, 140.6, 139.4, 138.2 (d, J_(CF)=3.7 Hz), 132.4 (dt, J_(CF)=8.6, 2.0 Hz), 130.6, 126.4 (dt, J_(CF)=6.1, 3.1 Hz), 124.3, 123.2 (dt, J_(CF)=23.2, 12.9 Hz), 121.4, 120.7, 117.7 (d, J_(CF)=20.8 Hz), 112.6 (dt, J_(CF)=236.3, 4.5 Hz); HRMS (ES⁺) m/z calc'd. for C₁₇H₁₁F₃N₅O₂ (M+H)⁺374.0859, found 374.0855.

Example 115. Synthesis of 6-((3-(6-(Trifluoromethyl)pyridin-3-yl)phenyl)amino)-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-ol (1-115)

Compound 1-115 was synthesized by procedure 1-E using 1-102 to yield 1-115 in 11% as an off-white solid: ¹H NMR ((CD₃)₂CO, 500 MHz) δ 11.97 (br s, 1H), 9.69 (s, 1H), 9.10-9.09 (m, 1H), 8.52-8.51 (m, 1H), 8.39-8.35 (m, 2H), 7.99 (d, J=8.1 Hz, 1H), 7.69-7.65 (m, 2H); ¹⁹F NMR ((CD₃)₂CO, 376 MHz) δ−68.23 (s, 3F); ¹³C NMR ((CD₃)₂CO, 125 MHz) δ153.7, 151.5, 150.4, 149.3, 147.4 (q, J_(CF)=34.2 Hz), 145.3, 139.9, 139.7, 137.9, 136.8, 130.9, 124.7, 122.9 (q, J_(CF)=273.1 Hz), 122.5, 121.7 (q, J_(CF)=2.8 Hz), 121.0; HRMS (ES⁺) m/z calc'd. for C₁₆H₁₀F₃N₆O₂ (M+H)⁺375.0812, found 375.0815.

Example 116. Synthesis of 6-((4-Fluoro-3-(6-(trifluoromethyl)pyridin-3-yl)phenyl)amino)-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-ol (1-116)

The requisite aniline was prepared by procedure 1-G to yield crude 4-fluoro-3-(6-(trifluoromethyl)pyridin-3-yl)aniline Product 1-116 was synthesized using the crude aniline by procedure 1-A in 44% as a light yellow powder: ¹H NMR ((CD₃)₂CO, 400 MHz) δ 12.09 (br s, 1H), 9.73 (s, 1H), 9.01-9.00 (m, 1H), 8.40-8.32 (m, 3H), 8.03 (dd, J=8.2, 0.9 Hz, 1H), 7.48-7.43 (m, 1H); ¹⁹F NMR ((CD₃)₂CO, 376 MHz) δ−68.38 (s, 3F), −123.27-−123.32 (m, 1F); ¹³C NMR ((CD₃)₂CO, 125 MHz) δ 157.5 (d, J_(CF)=247.0 Hz), 153.5, 151.4, 150.7 (d, J_(CF)=3.9 Hz), 150.3, 147.7 (q, J_(CF)=34.1 Hz), 145.1, 138.9 (d, J_(CF)=3.5 Hz), 135.8 (d, J_(CF)=1.6 Hz), 135.3, 125.3 (d, J_(CF)=14.5 Hz), 124.8 (d, J_(CF)=8.5 Hz), 124.5, 122.8 (q, J_(CF)=272.8 Hz), 121.5, 117.6 (d, J_(CF)=23.9 Hz); HRMS (ESI⁺) m/z calc'd. for C₁₆H₉F₄N₆O₂ (M+H)⁺393.0718, found 393.0716.

Example 117. Synthesis of 6-((4-(Trifluoromethoxy)-3-(6-(trifluoromethyl)pyridin-3-yl)phenyl)amino)-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-ol (1-117)

The requisite aniline was prepared by procedure 1-G to yield crude 4-(trifluoromethoxy)-3-(6-(trifluoromethyl)pyridin-3-yl)aniline Product 1-117 was synthesized using the crude aniline by procedure 1-A in 21% as a light yellow solid: ¹H NMR ((CD₃)₂CO, 500 MHz) δ 11.98 (br s, 1H), 9.80 (s, 1H), 8.95 (d, J=2.1 Hz, 1H), 8.47 (dd, J=9.0, 2.7 Hz, 1H), 8.40 (d, J=2.7 Hz, 1H), 8.29 (dd, J=8.2, 2.2 Hz, 1H), 8.04 (d, J=8.1 Hz, 1H), 7.67 (dd, J=9.0, 1.6 Hz, 1H); ¹⁹F NMR ((CD₃)₂CO, 376 MHz) δ 58.32 (d, J=1.5 Hz, 3F), −68.39 (s, 3F); ¹³C NMR ((CD₃)₂CO, 125 MHz) δ 153.47, 151.55, 150.93, 150.18, 147.83 (q, J_(CF)=34.7 Hz), 145.19, 143.27, 139.34, 138.33, 136.45, 131.90, 124.97, 124.01, 123.42, 122.77 (q, J_(CF)=273.3 Hz), 121.34 (q, J_(CF)=2.6 Hz), 121.33 (d, J_(CF)=256.9 Hz); HRMS (ESI⁺) m/z calc'd. for C₁₇H₉F₆N₆O₃ (M+H)⁺459.0635, found 459.0634.

Example 118. Synthesis of 6-((9,9-Dimethyl-9H-fluoren-2-yl)amino)-[1,2,5]oxadiazolo[3,4-B]pyrazin-5-ol (1-118)

Compound 1-118 was synthesized by procedure 1-A to yield 1-118 in 49% as a yellow solid: ¹H NMR ((CD₃)₂CO, 500 MHz) δ 12.07 (br s, 1H), 9.58 (s, 1H), 8.27 (d, J=2.1 Hz, 1H), 8.19 (dd, J=8.2, 2.1 Hz, 1H), 7.89 (d, J=8.3 Hz, 1H), 7.82 (dd, J=6.7, 1.4 Hz, 1H), 7.56-7.54 (m, 1H), 7.37-7.31 (m, 2H), 1.52 (s, 6H); ¹³C NMR ((CD₃)₂CO, 125 MHz) δ155.3, 154.6, 153.7, 150.9, 150.5, 145.1, 139.5, 138.0, 137.0, 128.1, 128.0, 123.6, 121.2, 120.8, 116.7; HRMS (ES⁻) m/z calc'd. for C₁₉H₁₄N₅O₂ (M−H)⁻344.1153, found 344.1122.

Example 119. Synthesis of 6-((3′,5′-Difluoro-[1,1′-biphenyl]-3-yl)amino)-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-ol (1-119)

The requisite aniline was prepared by procedure 1-G to yield 3′,5′-difluoro-[1,1′-biphenyl]-3-amine in 85% as an orange oil: ¹H NMR ((CD₃)₂CO, 400 MHz) δ 7.24-7.18 (m, 2H), 7.18-7.14 (m, 1H), 6.99-6.96 (m, 1H), 6.95 (dt, J=9.1, 2.4 Hz, 1H), 6.89 (ddd, J=7.6, 1.8, 1.0 Hz, 1H), 6.73 (ddd, J=8.0, 2.3, 1.0 Hz, 1H), 4.80 (br s, 2H); ¹⁹F NMR ((CD₃)₂CO, 376 MHz) δ−111.48-−111.55 (m, 2F).

Product 1-119 was synthesized using acetone as the solvent by procedure 1-A in 43% as an off-white solid: ¹H NMR ((CD₃)₂CO, 500 MHz) δ 12.09 (br s, 1H), 9.62 (s, 1H), 8.40 (d, J=2.3 Hz, 1H), 8.35-8.30 (m, 1H), 7.61-7.57 (m, 2H), 7.40-7.35 (m, 2H), 7.06 (tt, J=9.1, 2.4 Hz, 1H); ¹⁹F NMR ((CD₃)₂CO₃ 376 MHz) δ−110.82-−110.90 (m, 2F); ¹³C NMR ((CD₃)₂CO₃ 125 MHz) δ 164.4 (dd, J_(CF)=246.5, 13.5 Hz), 153.6, 151.3, 150.4, 145.1, 145.0 (t, J_(CF)=9.5 Hz), 139.9 (t, J_(CF)=2.7 Hz), 139.4, 130.6, 124.3, 122.1, 120.7, 110.7 (dd, J_(CF)=20.0, 6.3 Hz), 103.5 (t, J_(CF)=25.9 Hz); HRMS (ES⁻) m/z calc'd. for C₁₆H₈F₂N₅O₂ (M−H)⁻340.0652, found 340.0642.

Example 120. Synthesis of 6-((3-(Benzo[D][1,3]dioxol-5-yl)phenyl)amino)-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-ol (1-120)

The requisite aniline was prepared by procedure 1-G to yield 3-(benzo[d][1,3]dioxol-5-yl)aniline in 62% as a yellow oil: ¹H NMR ((CD₃)₂CO, 400 MHz) δ 7.14-7.05 (m, 3H), 6.90-6.87 (m, 2H), 6.79 (ddd, J=7.6, 1.8, 1.0 Hz, 1H), 6.62 (ddd, J=8.0, 2.3, 1.0 Hz, 1H), 6.02 (s, 2H), 4.67 (br s, 2H).

Product 1-120 was synthesized using acetone as the solvent by procedure 1-A in 54% as a brown solid: ¹H NMR ((CD₃)₂SO, 500 MHz) δ13.31 (br s, 1H), 10.27 (s, 1H), 8.24 (t, J=2.0 Hz, 1H), 8.06 (dt, J=8.1, 1.6 Hz, 1H), 7.48-7.41 (m, 2H), 7.23 (d, J=1.8 Hz, 1H), 7.16 (dd, J=8.1, 1.8 Hz, 1H), 7.04 (d, J=8.0 Hz, 1H), 6.08 (s, 2H); ¹³C NMR ((CD₃)₂S0, 125 MHz) δ 153.1, 150.9, 149.7, 148.1, 147.1, 144.6, 140.3, 138.3, 134.1, 129.2, 122.8, 120.22, 120.19, 119.9, 108.8, 107.0, 101.2; HRMS (ES⁻) m/z calc'd. for C₁₇H₁₀N₅O₄ (M−H)⁻348.0738, found 348.0735.

Example 121. Synthesis of 6-((3′,5′-Difluoro-[1,1′-biphenyl]-4-yl)amino)-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-ol (1-121)

The requisite aniline was prepared by procedure 1-G to yield crude 3′,5′-difluoro-[1,1′-biphenyl]-4-amine as yellow solid.

Product 1-121 was synthesized using acetone as the solvent by procedure 1-A in 40% as a burnt-orange solid: ¹H NMR ((CD₃)₂CO, 500 MHz) δ 12.07 (br s, 1H), 9.66 (s, 1H), 8.30-8.27 (m, 2H), 7.86-7.83 (m, 2H), 7.41-7.36 (m, 2H), 7.01 (tt, J=9.1, 2.3 Hz, 1H); ¹⁹F NMR ((CD₃)₂CO, 376 MHz) δ 111.00-−111.09 (s, 2F); ¹³C NMR ((CD₃)₂CO, 125 MHz) δ 164.4 (dd, J_(CF)=246.2, 13.3 Hz), 153.6, 151.3, 150.4, 145.1, 144.8 (t, J_(CF)=9.7 Hz), 139.2, 135.6 (t, J_(CF)=2.5 Hz), 128.3, 122.5, 110.4 (dd, J_(CF)=19.9, 6.3 Hz), 103.1 (t, J_(CF)=26.0 Hz); HRMS (ES⁻) m/z calc'd. for C₁₆H₈F₂N₅O₂ (M−H)⁻ 340.0652, found 340.0643.

Example 122. Synthesis of 6-((4-(Benzo[D][1,3]dioxol-5-yl)Phenyl)amino)-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-ol (1-122)

The requisite aniline was prepared by procedure 1-G to yield 4-(benzo[d][1,3]dioxol-5-yl)aniline in 61% as a yellow solid: ¹H NMR ((CD₃)₂CO, 400 MHz) δ 7.32-7.28 (m, 2H), δ 7.03 (dd, J=1.9, 0.5 Hz, 1H), 7.01 (dd, J=8.0, 1.8 Hz, 1H), 6.85 (dd, J=8.0, 0.5 Hz, 1H), 6.74-6.70 (m, 2H), 5.99 (s, 2H), 4.70 (br s, 2H).

Product 1-122 was synthesized using acetone as the solvent by procedure 1-A in 61% as a light brown solid: ¹H NMR ((CD₃)₂CO, 400 MHz) δ 12.04 (br s, 1H), 9.58 (s, 1H), 8.21-8.18 (m, 2H), 7.71-7.69 (m, 2H), 7.82-7.78 (m, 2H), 7.22-7.19 (m, 2H), 6.95 (d, J=8.0 Hz, 1H), 6.05 (s, 2H); ¹³C NMR ((CD₃)₂CO, 125 MHz) δ 153.6, 151.1, 150.5, 149.3, 148.2, 145.1, 138.2, 137.7, 135.4, 127.8, 122.4, 121.1, 109.4, 107.9, 102.2; HRMS (ES⁻) m/z calc'd. for C₁₇H₁₀N₅O₄ (M−H)⁻348.0738, found 348.0739.

Example 123. Synthesis of 4-(4-((6-Hydroxy-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-yl)amino)phenyl)thiophene-2-carbonitrile (1-123)

The requisite aniline was prepared by procedure 1-G to yield crude 4-(4-aminophenyl)thiophene-2-carbonitrile as a beige solid.

Product 1-123 was synthesized using acetone as the solvent by procedure 1-A in 41% as a yellow solid: ¹H NMR ((CD₃)₂CO, 500 MHz) δ 11.94 (br s, 1H), 9.63 (s, 1H), 8.31-8.29 (m, 1H), 8.26-8.21 (m, 3H), 7.89-7.84 (m, 2H); ¹³C NMR ((CD₃)₂CO, 125 MHz) δ 153.6, 151.2, 150.4, 145.2, 143.1, 138.7, 137.5, 131.2, 128.5, 127.8, 122.6, 114.7, 111.1; HRMS (ES⁻) m/z calc'd. for C₁₅H₇N₆O₂S (M−H)⁻ 335.0357, found 335.0367.

Example 124. Synthesis of 6-((3,4′-Difluoro-[1,1′-biphenyl]-4-yl)amino)-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-ol (1-124)

The requisite aniline was prepared by procedure 1-G to yield 3,4′-difluoro-[1,1′-biphenyl]-4-amine in 74% as a yellow solid: ¹H NMR ((CD₃)₂CO, 400 MHz) δ 7.63-7.58 (m, 2H), 7.27 (dd, J=12.8, 2.1 Hz, 1H), 7.21 (ddd, J=8.2, 2.1, 0.7 Hz, 1H), 7.19-7.13 (m, 2H), 6.92 (dd, J=9.4, 8.2 Hz, 1H), 4.81 (br s, 2H); ¹⁹F NMR ((CD₃)₂CO, 376 MHz) δ−118.62-−118.70 (m, 1F), −136.99 (dd, J=12.8, 9.5 Hz, 1F).

Product 1-124 was synthesized using acetone as the solvent by procedure 1-A in 11% as a burnt-orange solid: ¹H NMR ((CD₃)₂CO, 500 MHz) δ12.17 (br s, 1H), 9.28 (s, 1H), 8.60 (t, J=8.5 Hz, 1H), 7.82-7.76 (m, 2H), 7.65-7.61 (m, 2H), 7.29-7.24 (m, 2H); ¹⁹F NMR ((CD₃)₂CO, 376 MHz) δ−116.22-−116.29 (m, 1F), −128.72-−128.78 (m, 1F); ¹³C NMR ((CD₃)₂CO, 125 MHz) δ163.7 (d, J_(CF)=245.6 Hz), 155.2 (d, J_(CF)=245.8 Hz), 153.6, 151.4, 150.3, 145.2, 139.0 (d, J_(CF)=7.6 Hz), 136.2 (d, J_(CF)=2.7 Hz), 129.7 (d, J_(CF)=8.3 Hz), 125.5 (d, J_(CF)=10.6 Hz), 124.3, 123.8 (d, J_(CF)=3.2 Hz), 116.6 (d, J_(CF)=21.6 Hz), 114.4 (d, J_(CF)=20.4 Hz); HRMS (ESI⁻) m/z calc'd. for C₁₆H₈F₂N₅O₂ (M−H)⁻ 340.0652, found 340.0654.

Example 125. Synthesis of 6-((2,4′-Difluoro-[1,1′-biphenyl]-4-yl)amino)-[1,2,5]oxadiazolo[3,4-B]pyrazin-5-ol (1-125)

The requisite aniline was prepared by procedure 1-G to yield 2,4′-difluoro-[1,1′-biphenyl]-4-amine in 80% as a colorless solid: ¹H NMR ((CD₃)₂CO₃ 400 MHz) δ 7.52-7.47 (m, 2H), 7.20-7.13 (m, 3H), 6.57 (dd, J=8.3, 2.3 Hz, 1H), 6.50 (dd, J=13.5, 2.2 Hz, 1H), 5.08 (br s, 2H); ¹⁹F NMR ((CD₃)₂CO₃ 376 MHz) δ−118.18-−118.27 (m, 1F), −119.93 (dd, J=13.4, 9.3 Hz, 1F).

Product 1-125 was synthesized using acetone as the solvent by procedure 1-A in 52% as a yellow solid: ¹H NMR ((CD₃)₂CO₃ 500 MHz) δ 12.11 (br s, 1H), 9.73 (s, 1H), 8.24 (dd, J=13.3, 2.2 Hz, 1H), 8.01 (dd, J=8.5, 2.2 Hz, 1H), 7.68-7.64 (m, 2H), 7.60 (t, J=8.7 Hz, 1H), 7.29-7.24 (m, 2H); ¹⁹F NMR ((CD₃)₂CO₃ 376 MHz) δ 116.05-116.13 (m, 1F), 117.541 (dd, J=13.4, 8.9 Hz, 1F); ¹³C NMR ((CD₃)₂CO₃ 125 MHz) δ 163.3 (d, J_(CF)=245.6 Hz), 160.2 (d, J_(CF)=245.0 Hz), 153.4, 151.4, 150.2, 145.1, 139.6 (d, J_(CF)=11.3 Hz), 132.4 (d, J_(CF)=3.2 Hz), 131.71 (d, J_(CF)=3.2 Hz), 131.65 (d, J_(CF)=3.8 Hz), 124.9 (d, J_(CF)=13.6 Hz), 118.3 (d, J_(CF)=3.2 Hz), 116.2 (d, J_(CF)=21.6 Hz), 109.6 (d, J_(CF)=28.8 Hz); HRMS (ESI⁻) m/z calc'd. for C₁₆H₈F₂N₅O₂ (M−H)⁻340.0652, found 340.0644.

Example 126. Synthesis of 6-((3-(2,2-Difluorobenzo[D][1,3]dioxol-5-yl)phenyl)amino)-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-ol (1-126)

The requisite aniline was prepared by procedure 1-G to yield 3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)aniline in 95% as an oil: ¹H NMR ((CD₃)₂CO₃ 400 MHz) δ 7.47 (dd, J=1.8, 0.6 Hz, 1H), 7.40 (ddd, J=8.3, 1.8, 0.6 Hz, 1H), 7.32 (dt, J=8.5, 0.6 Hz, 1H), 7.14 (t, J=7.8 Hz, 1H), 6.94-6.92 (m, 1H), 6.84 (ddd, J=7.7, 1.9, 1.0 Hz, 1H), 6.69 (ddd, J=8.0, 2.3, 1.0 Hz, 1H), 4.77 (br s, 2H); ¹⁹F NMR ((CD₃)₂CO₃ 376 MHz) δ-51.20 (d, J=1.8 Hz, 2F).

Product 1-126 was synthesized using acetone as the solvent by procedure 1-A in 45% as an off-white solid: ¹H NMR ((CD₃)₂CO₃ 500 MHz) δ 12.08 (br s, 1H), 9.60 (s, 1H), 8.36 (t, J=2.0 Hz, 1H), 8.26-8.24 (m, 1H), 7.62 (d, J=1.8 Hz, 1H), 7.58-7.51 (m, 3H), 7.41 (d, J=8.3 Hz, 1H); ¹⁹F NMR ((CD₃)₂CO, 376 MHz) δ-51.14 (s, 2F); ¹³C NMR ((CD₃)₂CO, 125 MHz) δ 153.6, 151.3, 150.4, 145.1, 145.0, 144.0, 141.2, 139.3, 138.4, 132.6 (t, J_(CF)=252.7 Hz), 130.5, 124.4, 123.9, 121.3, 120.7, 111.0, 109.4; HRMS (ESI⁻) m/z calc'd. for C₁₇H₈F₂N₅O₄ (M−H)⁻ 384.0550, found 384.0554.

Example 127. Synthesis of 2-((6-Hydroxy-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-yl)amino)-9H-fluoren-9-One (1-127)

Compound 1-127 was synthesized by procedure 1-A at 75° C. to yield 1-127 in 32% as an orange solid: ¹H NMR ((CD₃)₂SO, 500 MHz) δ 13.34 (br s, 1H), 10.52 (s, 1H), 8.42 (d, J=2.0 Hz, 1H), 8.20 (dd, J=8.2, 2.1 Hz, 1H), 7.84 (d, J=8.1 Hz, 1H), 7.76 (d, J=7.6 Hz, 1H), 7.63-7.60 (m, 2H), 7.36 (t, J=7.4 Hz, 1H); ¹³C NMR ((CD₃)₂SO, 125 MHz) δ192.9, 152.9, 151.0, 149.5, 144.6, 143.9, 139.8, 139.1, 135.6, 133.9, 133.6, 129.1, 127.7, 124.1, 121.5, 121.0, 117.2; HRMS (ES⁺) fizz calc'd. for C₁₇H₁₀N₅O₃ (M+H)⁺332.0778, found 332.0782.

Example 128. Synthesis of 6-((4′-Fluoro-3′-methoxy-[1,1′-biphenyl]-4-yl)amino)-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-ol (1-128)

The requisite aniline was prepared by procedure 1-G to yield 4′-fluoro-3′-methoxy-[1,1′-biphenyl]-4-amine in 24% as a yellow oil: ¹H NMR ((CD₃)₂CO, 400 MHz) δ 7.37-7.35 (m, 2H), 7.27-7.24 (m, 1H), 7.14-7.05 (m, 2H), 6.75-6.72 (m, 2H), 4.76 (br s, 2H), 3.95 (s, 3H); ¹⁹F NMR ((CD₃)₂CO, 376 MHz) δ−141.11-−141.18 (m, 1F).

Product 1-128 was synthesized using acetone as the solvent by procedure 1-A in 60% as a yellow solid: ¹H NMR ((CD₃)₂CO, 500 MHz) δ 12.06 (br s, 1H), 9.61 (s, 1H), 8.24-8.21 (m, 2H), 7.78-7.75 (m, 2H), 7.45 (dd, J=8.3, 2.1 Hz, 1H), 7.28-7.20 (m, 2H), 4.01 (s, 3H); ¹⁹F NMR ((CD₃)₂CO, 376 MHz) δ−138.81-−138.87 (m, 1F); ¹³C NMR ((CD₃)₂CO, 125 MHz) δ 153.6, 152.8 (d, J_(CF)=245.0 Hz), 151.2, 150.5, 148.9 (d, J_(CF)=10.8 Hz), 145.1, 138.1, 138.0 (d, J_(CF)=3.7 Hz), 137.7, 128.2, 122.5, 119.8 (d, J_(CF)=6.8 Hz), 116.9 (d, J_(CF)=18.5 Hz), 113.1 (d, J_(CF)=2.0 Hz), 56.6; HRMS (ES⁺) m/z calc'd. for C₁₇H₁₃FN₅O₃ (M+H)⁺354.0997, found 354.1005.

Example 129. Synthesis of 4-Fluoro-4′-((6-hydroxy-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-yl)amino)-[1,1′-biphenyl]-3-carbonitrile (1-129)

The requisite aniline was prepared by procedure 1-G to yield 4′-amino-4-fluoro-[1,1′-biphenyl]-3-carbonitrile in 90% as an off-white solid: ¹H NMR ((CD₃)₂CO, 400 MHz) δ 7.97-7.95 (m, 1H), 7.94-7.91 (m, 1H), 7.46-7.40 (m, 3H), 6.79-6.76 (m, 2H), 4.92 (br s, 2H); ¹⁹F NMR ((CD₃)₂CO, 376 MHz) δ−115.18-−115.25 (m, 1F).

Product 1-129 was synthesized by procedure 1-A in 67% as a yellow solid: ¹H NMR ((CD₃)₂S0, 500 MHz) δ 13.32 (br s, 1H), 10.39 (s, 1H), 8.27 (dd, J=6.1, 2.5 Hz, 1H), 8.19-8.16 (m, 2H), 8.13-8.09 (m, 1H), 7.81-7.77 (m, 2H), 7.61 (t, J=9.0 Hz, 1H); ¹⁹F NMR ((CD₃)₂CO, 376 MHz) δ −112.69-−112.74 (m, 1F); ¹³C NMR ((CD₃)₂SO, 125 MHz) δ 161.8 (d, J_(CF)=255.9 Hz), 153.0, 150.8, 149.6, 144.6, 138.1, 137.0 (d, J_(CF)=3.3 Hz), 133.9 (d, J_(CF)=8.6 Hz) 133.1, 131.5, 127.1, 122.1, 117.1 (d, J_(CF)=19.5 Hz), 114.1, 100.8 (d, J_(CF)=15.4 Hz); HRMS (ES⁻) m/z calc'd. for C₁₇H₈FN₆O₂ (M−H)⁻ 347.0698, found 347.0712.

Example 130. Synthesis of 6-((4′-(Trifluoromethyl)-[1,1′-biphenyl]-4-yl)amino)-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-ol (1-130)

Compound 1-130 was synthesized by procedure 1-F using 1-19 to yield 1-130 in 23% as a yellow solid: ¹H NMR (400 MHz, Acetone-d₆) δ 9.66 (s, 1H), 8.32-8.28 (m, 2H), 7.97-7.93 (m, 2H), 7.88-7.80 (m, 4H); ¹⁹F NMR (376 MHz, Acetone-d₆) δ−62.90 (s, 3F); ¹³C NMR (126 MHz, Acetone-d₆) δ 153.56, 151.17, 150.30, 145.12, 144.83 (q, J=1.2 Hz), 138.90, 136.41, 129.39 (q, J=32.7 Hz), 128.39, 128.06, 127.55 (q, J=274.5 Hz), 126.55 (q, J=4.0 Hz), 122.48; HRMS (ESI⁺) m/z calc'd. for C₁₇H₁₁F₃N₅O₂ (M+H)⁺374.0859, found 374.0863.

Example 131. Synthesis of 6-((4′-(Trifluoromethyl)-[1,1′-biphenyl]-3-yl)amino)-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-ol (1-131)

Compound 1-131 was synthesized by procedure 1-B to yield 1-131 in 55% as a pink solid: ¹H NMR (400 MHz, Acetone-d₆) δ 9.64 (s, 1H), 8.49-8.43 (m, 1H), 8.32-8.24 (m, 1H), 7.93 (d, J=8.1 Hz, 2H), 7.84 (d, J=8.1 Hz, 2H), 7.64-7.55 (m, 2H); ¹³C NMR (101 MHz, Acetone-d₆) δ Rotamers 153.57*, 153.55, 151.33*, 151.22 (d, J=3.6 Hz), 150.34, 145.19 (q, J=1.6 Hz), 145.07, 140.91, 139.40*, 139.31, 130.56, 129.90 (q, J=32.1 Hz), 128.46, 126.67 (q, J=4.0 Hz), 125.42 (q, J=271.6 Hz), 124.53 (q, J=1.7 Hz), 121.87, 121.78, 120.84, 120.75; HRMS (ESI⁺) m/z calc'd. for C₁₇H₁₁F₃N₅O₂ (M+H)⁺374.0859, found 374.0871.

Example 132. Synthesis of 6-((4′-Methyl-[1,1′-biphenyl]-3-yl)amino)-[1,2,5]oxadiazolo[3,4-B]Pyrazin-5-ol (1-132)

Compound 1-132 was synthesized by procedure 1-B to yield 1-132 in 64% as a pink solid: ¹H NMR (400 MHz, Acetone-d₆) δ 11.36 (s, 1H), 9.57 (s, 1H), 8.36 (t, J=1.8 Hz, 1H), 8.17 (dt, J=7.5, 2.0 Hz, 1H), 7.62-7.58 (m, 2H), 7.55-7.47 (m, 2H), 7.33-7.27 (m, 2H), 2.37 (s, 3H); ¹³C NMR (101 MHz, Acetone-d₆) δ Rotamers 153.59, 153.55*, 151.21, 151.12*, 150.39, 145.04, 142.49, 139.13, 139.04*, 138.38, 138.21, 130.42, 130.21, 127.59, 124.10, 124.09*, 120.63, 120.54, 120.37, 120.28, 21.06; HRMS (ESI⁺) m/z calc'd. for C₁₇H₁₄N₅O₂ (M+H)⁺320.1142, found 320.1137.

Example 133. Synthesis of 6-((4′-Chloro-[1,1′-biphenyl]-3-yl)amino)-[1,2,5]oxadiazolo[3,4-B]pyrazin-5-ol (1-133)

Compound 1-133 was synthesized by procedure 1-F using 1-18 to yield 1-133 in 24% as a yellow solid: ¹H NMR (400 MHz, Acetone-d₆) δ 12.17 (s, 1H), 9.61 (s, 1H), 8.39 (t, J=2.1, 0.5 Hz, 3H), 8.28-8.19 (m, 1H), 7.79-7.69 (m, 2H), 7.64-7.46 (m, 2H); ¹³C NMR (101 MHz, Acetone-d₆) δ 153.66, 151.37, 150.45, 145.15, 141.27, 140.14, 139.38, 134.20, 130.52, 129.93, 129.46, 124.31, 121.37, 120.61; HRMS (ESI⁺) m/z calc'd. for C₁₆H₁₁ClN₅O₂ (M+H)⁺340.0595, found 340.0595.

Example 134. Synthesis of 6-((4′-Fluoro-[1,1′-biphenyl]-3-yl)amino)-[1,2,5]oxadiazolo[3,4-B]pyrazin-5-ol (1-134)

Compound 1-134 was synthesized by procedure 1-B to yield 1-134 in 7% as a yellow solid: ¹H NMR (400 MHz, Acetone-d₆) δ 9.60 (s, 1H), 8.37 (t, J=2.0 Hz, 1H), 8.24-8.18 (m, 1H), 7.80-7.71 (m, 2H), 7.60-7.48 (m, 2H), 7.27 (t, J=9.0 Hz, 2H); ¹⁹F NMR (376 MHz, Acetone-d₆) δ−116.79-−116.91 (m, 1F); ¹³C NMR (126 MHz, DMSO-d₆) δ 162.02 (d, J_(CF)=244.4 Hz), 153.06, 150.90, 149.65, 144.58, 139.54, 138.38, 136.33 (d, J_(CF)=3.1 Hz), 129.34, 128.62 (d, J_(CF)=8.2 Hz), 123.02, 120.64, 120.11, 115.89 (d, J_(CF)=21.5 Hz); HRMS (ESI⁺) m/z calc'd. for C₁₆H₁₁FN₅O₂ (M+H)⁺324.0891, found 324.0893.

Example 135. Synthesis of 6-((3′-(Trifluoromethyl)-[1,1′-biphenyl]-3-yl)amino)-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-ol (1-135)

Compound 1-135 was synthesized by procedure 1-B to yield 1-135 in 4% as a yellow solid: ¹H NMR (400 MHz, Acetone-d₆) δ 11.68 (s, 1H), 9.67 (s, 1H), 8.47-8.42 (m, 1H), 8.36-8.28 (m, 1H), 8.07-7.99 (m, 2H), 7.79-7.72 (m, 2H), 7.65-7.59 (m, 2H); ¹⁹F NMR (376 MHz, Acetone-d₆) δ 63.10 (s, 3F); ¹³C NMR (126 MHz, Acetone-d₆) δ 153.61, 151.39, 150.39, 145.12, 142.36, 140.90, 139.46, 131.65 (d, J_(CF)=2.3 Hz), 131.63 (q, J_(CF)=32.5 Hz), 130.88, 130.62, 125.36 (d, J_(CF)=271.1 Hz), 125.17 (q, J_(CF)=4.3 Hz), 124.48, 124.34 (q, J_(CF)=4.3 Hz), 121.74, 120.86; HRMS (ESI⁺) m/z calc'd. for C₁₇H₁₁F₃N₅O₂ (M+H)⁺374.0859, found 374.0877.

Example 136. Synthesis of 6-((4′-(Trifluoromethoxy)-[1,1′-biphenyl]-3-yl)amino)-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-ol (1-136)

Compound 1-136 was synthesized by procedure 1-B to yield 1-136 in 1% as a yellow solid: ¹H NMR (400 MHz, Acetone-d₆) δ 12.15 (s, 1H), 9.62 (s, 1H), 8.42 (t, J=2.0 Hz, 1H), 8.25 (dt, J=7.7, 1.8 Hz, 1H), 7.88-7.81 (m, 2H), 7.62-7.53 (m, 2H), 7.51-7.43 (m, 2H); ¹⁹F NMR (376 MHz, Acetone-d₆) δ−58.56; HRMS (ESI⁺) m/z calc'd. for C₁₇H₁₁F₃N₅O₃ (M+H)⁺390.0809, found 390.0826.

Example 137. Synthesis of 6-((3′-Methoxy-[1,1′-biphenyl]-4-yl)amino)-[1,2,5]oxadiazolo[3,4-B]pyrazin-5-ol (1-137)

Compound 1-137 was synthesized by procedure 1-B to yield 1-137 in 25% as a yellow solid: ¹H NMR (400 MHz, Acetone-d₆) δ 12.07 (s, 1H), 9.60 (s, 1H), 8.27-8.19 (m, 2H), 7.80-7.74 (m, 2H), 7.38 (t, 1H), 7.30-7.23 (m, 2H), 6.94 (d, 1H), 3.88 (s, 3H); ¹³C NMR (101 MHz, Acetone-d₆) δ 161.30, 153.70, 151.20, 150.54, 145.19, 142.60, 138.37, 138.21, 130.87, 128.26, 122.51, 119.92, 113.81, 113.14, 55.66. HRMS (ESI⁺) m/z calc'd. for C₁₇H₁₄N₅O₃ (M+H)⁺336.1091, found 336.1092.

Alkoxy Series Example 138. Synthesis of 5-Chloro-6-methoxy-[1,2,5]oxadiazolo[3,4-b]pyrazine (1-138)

5,6-Dichloro-[1,2,5]oxadiazolo[3,4-b]pyrazine (1-2) (2.00 g) was dissolved in anhydrous THF (25 mL) and Et₃N (1.46 mL, 1 equiv.) was added. The solution was mixed and MeOH (0.9 equiv.) was added dropwise over a few minutes. The solution evolved into a slurry and was allowed to stir at room temperature for 30 min. The solvent was then removed under reduced pressure and purified by chromatography on SiO₂ (gradient: 5-15% EtOAc/hexanes) to yield 1-138 (68%) as a colorless solid.

Example 139. Synthesis of N-(3,5-Bis(trifluoromethyl)Phenyl)-6-methoxy-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-amine (1-139)

Compound 1-139 was synthesized by procedure 1-C using 1-138 to yield 1-139 in 89% as an off-white solid: ¹H NMR (500 MHz, Acetone-d₆) δ 10.02 (s, 1H), 8.76 (d, J=1.5 Hz, 2H), 7.93-7.75 (m, 1H), 4.27 (s, 3H); ¹⁹F NMR (376 MHz, Acetone-d₆) δ−63.57 (s 6F); ¹³C NMR (126 MHz, Acetone-d₆) δ 156.22, 151.28, 150.61, 147.92, 140.78, 132.63 (q, J=33.3 Hz), 124.30 (d, J=272.7 Hz), 122.30 (q, J=4.7 Hz), 118.56 (h, J=4.2 Hz), 56.75; HRMS (ESI⁺) m/z calc'd. for C₁₃H₈F₆N₅O₂ [M+H]⁺ 380.0577, found 380.0578.

Example 140. Synthesis of N-(2-Fluoro-3-(Trifluoromethyl)phenyl)-6-methoxy-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-amine (1-140)

Compound 1-140 was synthesized by procedure 1-C using 1-138 to yield 1-140 in 80% as a beige solid: ¹H NMR (400 MHz, Acetone-d₆) δ 9.38-9.25 (m, 1H), 8.54-8.42 (m, 1H), 7.66 (dddd, J=8.2, 6.6, 1.7, 0.8 Hz, 1H), 7.53 (tt, J=8.0, 1.1 Hz, 1H), 4.30 (s, 3H); ¹⁹F NMR (376 MHz, Acetone-d₆) δ−61.75 (d, J=13.0 Hz 3F), −126.91-−127.08 (m 1F); ¹³C NMR (101 MHz, Acetone-d₆) δ156.23, 152.35 (dq, J=256 Hz, 2.4, Hz), 151.59, 150.82, 148.32, 130.95 (d, J=1.8 Hz), 127.41 (d, J=10.6 Hz), 125.69 (d, J=5.0 Hz), 124.68 (q, J=4.8, 1.3 Hz), 123.58 (q, J=272.9 Hz), 56.81; HRMS (ESI⁺) m/z calc'd. for C₁₂H₈F₄N₅O₂ [M+H]+ 330.0609, found 330.0655.

Example 141. Synthesis of 6-Methoxy-N-(3-(trifluoromethoxy)phenyl)-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-amine (1-141)

Compound 1-141 was synthesized by procedure 1-C using 1-138 to yield 1-141 in 95% as a yellow solid: ¹H NMR (500 MHz, Acetone-d₆) δ 9.73 (s, 1H), 8.17 (td, J=2.2, 1.1 Hz, 1H), 8.08-7.95 (m, 1H), 7.56 (t, J=8.2 Hz, 1H), 7.17 (ddt, J=8.3, 2.3, 1.1 Hz, 1H), 4.23 (s, 3H); ¹⁹F NMR (376 MHz, Acetone-d₆) δ-58.50 (s 3F); ¹³C NMR (126 MHz, Acetone-d₆) δ 156.30, 151.57, 150.54, 149.99 (q, J=2.2 Hz), 147.70, 140.38, 131.22, 121.44 (q, J=257.9 Hz), 120.99, 117.84, 114.87, 56.56; HRMS (ESI⁺) m/z calc'd. for C₁₂H₉F₃N₅O₃ [M+H]+ 328.0652, found 328.0666.

Example 142. Synthesis of 6-Methoxy-N-(2-methyl-5-(trifluoromethyl)phenyl)-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-amine (1-142)

Compound 1-142 was synthesized by procedure 1-C using 1-138 to yield 1-142 in 93% as an off-white solid: ¹H NMR (500 MHz, Acetone-d₆) δ 9.28 (s, 1H), 8.09 (s, 1H), 7.58 (d, J=1.2 Hz, 2H), 4.28 (s, 3H), 2.45 (d, J=1.1 Hz, 3H); ¹⁹F NMR (376 MHz, Acetone-d₆) δ-62.80 (s 3F); ¹³C NMR (126 MHz, Acetone-d₆) δ 156.55, 151.95, 150.83, 148.91, 139.26 (d, J_(CF)=1.6 Hz), 137.13, 132.43, 129.07 (d, J_(CF)=32.4 Hz), 125.50 (d, J_(CF)=272.0 Hz), 124.08 (q, J_(CF)=4.0 Hz), 123.60 (q, J_(CF)=4.3 Hz), 56.65, 18.17; HRMS (ESI⁺) m/z calc'd. for C₁₃H₁₁F₃N₅O₂ [M+H]⁺ 326.0859, found 326.0906.

Example 143. Synthesis of N-(3-Fluorophenyl)-6-methoxy-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-amine (1-143)

Compound 1-143 was synthesized by procedure 1-C using 1-138 to yield 1-143 in 74% as a yellow solid: ¹H NMR (500 MHz, Acetone-d₆) δ 9.64 (s, 1H), 8.03 (dt, J=11.5, 2.3 Hz, 1H), 7.79-7.70 (m, 1H), 7.44 (td, J=8.3, 6.7 Hz, 1H), 6.97 (tt, J=8.5, 1.6 Hz, 1H), 4.21 (s, 3H); ¹⁹F NMR (376 MHz, Acetone-d₆) δ−113.03-−113.17 (m, 1F); ¹³C NMR (126 MHz, Acetone-d₆) δ163.47 (d, J_(CF)=242.0 Hz), 156.24, 151.58, 150.46, 147.54, 140.37 (d, J_(CF)=11.3 Hz), 131.14 (d, J_(CF)=9.6 Hz), 118.07 (d, J_(CF)=3.5 Hz), 112.23 (d, J_(CF)=21.5 Hz), 109.28 (d, J_(CF)=27.1 Hz), 56.52; HRMS (ESI⁺) m/z calc'd. for C₁₁H₉FN₅O₂ [M+H]⁺ 262.0735, found 262.0774.

Example 144. Synthesis of 6-Methoxy-N-(p-Tolyl)-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-amine (1-144)

Compound 1-144 was synthesized by procedure 1-C using 1-138 to yield 1-144 in 89% as a yellow solid: ¹H NMR (500 MHz, Acetone-d₆) δ 8.85 (s, 1H), 7.87-7.78 (m, 2H), 7.42-7.29 (m, 2H), 4.31 (s, 3H), 2.45 (s, 3H); ¹³C NMR (126 MHz, Acetone-d₆) δ185.23, 180.64, 179.30, 176.38, 164.91, 164.16, 158.88, 151.37, 146.81, 85.25, 49.52; HRMS (ESI⁺) m/z calc'd. for C₁₂H₁₂N₅O₂ [M+H]+ 258.0986, found 258.0990.

Example 145. Synthesis of 6-Methoxy-N-(4-methoxyphenyl)-[1,2,5]oxadiazolo[3,4-B]pyrazin-5-amine (1-145)

Compound 1-145 was synthesized by procedure 1-C using 1-138 to yield 1-145 in 90% as a yellow solid: ¹H NMR (500 MHz, Acetone-d₆) δ 8.83 (s, 1H), 7.88-7.81 (m, 2H), 7.13-7.06 (m, 2H), 4.31 (s, 3H), 3.92 (s, 3H); ¹³C NMR (126 MHz, Acetone-d₆) δ186.85, 185.32, 180.74, 179.36, 176.41, 159.58, 153.17, 146.82, 143.53, 85.23, 84.64; HRMS (ESI⁺) m/z calc'd. for C₁₂H₁₂N₅O₃ [M+H]+ 274.0935, found 274.0940.

Example 146. Synthesis of 6-Methoxy-N-Phenyl-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-amine (1-146)

Compound 1-146 was synthesized by procedure 1-C using 1-138 to yield 1-146 in 94% as a beige solid: ¹H NMR (500 MHz, Acetone-d₆) δ 8.90 (s, 1H), 8.00-7.94 (m, 2H), 7.59-7.51 (m, 2H), 7.38-7.32 (m, 1H), 4.32 (s, 3H); carbon; HRMS (ESI⁺) m/z calc'd. for C₁₁H₁₀N₅O₂ [M+H]⁺ 244.0829, found 244.0834.

Example 147. Synthesis of N-(2,3-Difluorophenyl)-6-methoxy-[1,2,5]oxadiazolo[3,4-B]pyrazin-5-amine (1-147)

Compound 1-147 was synthesized by procedure 1-C using 1-138 to yield 1-147 in 90% as an off-white solid: ¹H NMR (500 MHz, Acetone-d₆) δ 9.78 (s, 1H), 7.90-7.76 (m, 2H), 6.87 (tt, J=9.1, 2.3 Hz, 1H), 4.23 (s, 3H); ¹⁹F NMR (376 MHz, Acetone-d₆) δ−110.31-−110.43 (m 2F); ¹³C NMR (126 MHz, Acetone-d₆) δ 163.85 (dd, J=244.2, 14.9 Hz), 156.20, 151.42, 150.52, 147.71, 141.32 (t, J=13.8 Hz), 105.62-104.84 (m), 100.62 (t, J=26.2 Hz), 56.62; HRMS (ESI⁺) m/z calc'd. for C₁₁H₈F₂N₅O₂ [M+H]⁺ 280.0641, found 280.0645.

Example 148. Synthesis of N-(3,5-Difluorophenyl)-6-methoxy-[1,2,5]oxadiazolo[3,4-B]pyrazin-5-amine (1-148)

Compound 1-148 was synthesized by procedure 1-C using 1-138 to yield 1-148 in 98% as an off-white solid: ¹H NMR (500 MHz, Acetone-d₆) δ 9.09 (s, 1H), 7.93-7.85 (m, 1H), 7.34-7.19 (m, 2H), 4.27 (s, 3H); ¹⁹F NMR (376 MHz, Acetone-d₆) δ−139.41-−139.55 (m, 1F), −148.52-−148.79 (m, 1F); ¹³C NMR (126 MHz, Acetone-d₆) δ156.24, 151.66, 151.41 (dd, J=245.7, 11.2 Hz), 150.80, 148.32, 144.85 (dd, J=249.2, 14.4 Hz), 127.59 (dd, J=8.7, 1.9 Hz), 125.11 (dd, J=7.9, 5.0 Hz), 121.81 (d, J=3.5 Hz), 117.78, 115.38 (d, J=17.1 Hz), 56.75; HRMS (ESI⁺) m/z calc'd. for C₁₁H₈F₂N₅O₂ [M+H]⁺ 280.0641, found 280.0654.

Example 149. Synthesis of N-(4-Chlorophenyl)-6-methoxy-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-amine (1-149)

Compound 1-149 was synthesized by procedure 1-C using 1-138 to yield 1-149 in 96% as a beige solid: ¹H NMR (500 MHz, Acetone-d₆) δ 9.62 (s, 1H), 8.11-8.00 (m, 2H), 7.53-7.40 (m, 2H), 4.22 (s, 3H); ¹³C NMR (126 MHz, Acetone-d₆) δ156.37, 151.72, 150.56, 147.58, 137.61, 130.37, 129.62, 124.03, 56.50; HRMS (ESI⁺) m/z calc'd. for C₁₁H₉C₁N₅O₂ [M+H]⁺ 278.0439, found 278.0455.

Example 150. Synthesis Of N-(4-(tert-Butyl)phenyl)-6-methoxy-[1,2,5]oxadiazolo[3,4-B]pyrazin-5-amine (1-150)

Compound 1-150 was synthesized by procedure 1-C using 1-138 to yield 1-150 in 97% as a yellow solid: ¹H NMR (500 MHz, Acetone-d₆) δ 8.88 (s, 1H), 7.89-7.82 (m, 2H), 7.64-7.57 (m, 2H), 4.33 (s, 3H), 1.44 (s, 9H); ¹³C NMR (126 MHz, Acetone-d₆) δ 155.73, 151.12, 149.78, 148.61, 146.95, 134.54, 125.74, 121.74, 117.25, 55.71, 34.12, 30.47; HRMS (ESI⁺) m/z calc'd. for C₁₅H₁₈N₅O₂ [M+H]⁺ 300.1455, found 300.1468.

Example 151. Synthesis of N-(3-Fluoro-4-(trifluoromethoxy)phenyl)-6-methoxy-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-amine (1-151)

Compound 1-151 was synthesized by procedure 1-C using 1-138 to yield 1-151 in 97% as a beige solid: ¹H NMR (500 MHz, Acetone-d₆) δ 9.83 (s, 1H), 8.42-8.11 (m, 1H), 8.05-7.69 (m, 1H), 7.67-7.32 (m, 1H), 4.23 (s, 3H); ¹⁹F NMR (376 MHz, Acetone-d₆) δ−59.87 (d, J=5.2 Hz, 3F), (s, 1 F); ¹³C NMR (126 MHz, Acetone-d₆) δ 156.28 (d, J_(CF)=4.7 Hz), 154.88 (d, J_(CF)=248.8 Hz), 151.48 (d, J_(CF)=3.6 Hz), 150.58 (d, J_(CF)=3.7 Hz), 147.70 (d, J_(CF)=5.4 Hz), 139.50-139.12 (m), 133.31-132.85 (m), 125.10 (d, J_(CF)=2.4 Hz), 121.48 (d, J_(CF)=256.8 Hz), 118.81, 111.56-110.66 (m), 56.61; HRMS (ESI⁺) m/z calc'd. for C₁₂H₈F₄N₅O₃ [M+H]+ 346.0558, found 346.0568.

Example 152. Synthesis of 6-Methoxy-N-(naphthalen-2-yl)-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-amine (1-152)

Compound 1-152 was synthesized by procedure 1-C using 1-138 to yield 1-152 in 97% as a yellow solid: ¹H NMR (400 MHz, Acetone-d₆) δ 9.69 (s, 1H), 8.81-8.77 (m, 1H), 8.00-7.86 (m, 4H), 7.58-7.44 (m, 2H), 4.26 (app d, J=0.5 Hz, 3H); ¹³C NMR (101 MHz, Acetone-d₆) δ 156.51, 151.91, 150.62, 147.68, 136.27, 134.59, 131.98, 129.40, 128.70, 128.47, 127.54, 126.42, 122.24, 119.47, 56.50; HRMS (ESI⁺) m/z calc'd. for C₁₅H₁₂N₅O₂ [M+H]+ 294.0986, found 294.0992.

Example 153. Synthesis Of N-(4-Ethylphenyl)-6-methoxy-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-amine (1-153)

Compound 1-153 was synthesized by procedure 1-C using 1-138 to yield 1-153 in 57% as a yellow solid: ¹H NMR (500 MHz, Acetone-d₆) δ 9.46 (s, 1H), 7.96-7.85 (m, 2H), 7.36-7.20 (m, 2H), 4.23 (s, 3H), 2.66 (q, J=7.6 Hz, 2H), 1.24 (t, J=7.6 Hz, 3H); ¹³C NMR (126 MHz, Acetone-d₆) δ 156.43, 151.94, 150.52, 147.46, 142.04, 136.31, 128.93, 122.60, 56.41, 28.90, 16.01; HRMS (ESI⁺) m/z calc'd. for C₁₃H₁₄N₅O₂ [M+H]⁺ 272.1142, found 272.1158.

Example 154. N-(3-Fluoro-4-pentylphenyl)-6-methoxy-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-amine (1-154)

Compound 1-154 was synthesized by procedure 1-C using 1-138 to yield 1-154 in 68% as a yellow solid: ¹H NMR (500 MHz, Acetone-d₆) δ 9.61 (s, 1H), 7.99 (dd, J=12.4, 2.2 Hz, 1H), 7.71 (dd, J=8.3, 2.2 Hz, 1H), 7.33 (t, J=8.5 Hz, 1H), 4.24 (s, 3H), 2.66 (t, J=7.7 Hz, 2H), 1.72-1.53 (m, 2H), 1.43-1.31 (m, 4H), 1.00-0.88 (m, 3H); ¹⁹F NMR (376 MHz, Acetone-d₆) δ−118.57-−118.67 (m, 1F); ¹³C NMR (126 MHz, Acetone-d₆) δ 161.43 (d, J_(CF)=241.7 Hz), 156.34, 151.73, 150.52, 147.50, 138.02 (d, J_(CF)=11.3 Hz), 131.57 (d, J_(CF)=6.6 Hz), 126.77 (d, J_(CF)=16.7 Hz), 118.06 (d, J_(CF)=3.6 Hz), 109.32 (d, J_(CF)=28.3 Hz), 56.49, 32.17, 29.53, 29.10, 23.10, 14.27; HRMS (ESI⁺) m/z calc'd. for C₁₆H₁₉FN₅O₂ [M+H]+ 332.1517, found 332.1533.

Example 155. Synthesis of N-(2-Fluoro-4-pentylphenyl)-6-methoxy-[1,2,5]oxadiazolo[3,4-B]pyrazin-5-amine (1-155)

Compound 1-155 was synthesized by procedure 1-C using 1-138 to yield 1-155 in 90% as a yellow solid: ¹H NMR (500 MHz, Acetone-d₆) δ 9.08 (s, 1H), 8.08 (t, J=8.3 Hz, 1H), 7.25-7.03 (m, 2H), 4.28 (s, 3H), 2.74-2.59 (m, 2H), 1.74-1.51 (m, 2H), 1.46-1.19 (m, 4H), 0.91 (t, J=6.8 Hz, 3H); ¹⁹F NMR (376 MHz, Acetone-d₆) δ−126.34 (dd, J=11.6, 8.2 Hz); ¹³C NMR (126 MHz, Acetone-d₆) δ 156.25, 155.81 (d, J_(CF)=246.6 Hz), 151.82, 150.68, 148.02, 143.68 (d, J_(CF)=7.3 Hz), 125.90 (d, J_(CF)=1.4 Hz), 125.16 (d, J_(CF)=3.6 Hz), 123.28 (d, J_(CF)=11.7 Hz), 116.08 (d, J_(CF)=19.2 Hz), 56.68, 35.80 (d, J_(CF)=1.8 Hz), 32.08, 31.65, 23.11, 14.29; HRMS (ESI⁺) m/z calc'd. for C₁₆H₁₉FN₅O₂ [M+H]+ 332.1517, found 332.1527.

Example 156. Synthesis of 6-Methoxy-N-(4-(trifluoromethoxy)phenyl)-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-amine (1-156)

Compound 1-156 was synthesized by procedure 1-C using 1-138 to yield 1-156 in 66% as a yellow solid: ¹H NMR (400 MHz, Acetone-d₆) δ 9.70 (brs, 1H), 8.18-8.13 (m, 2H), 7.44-7.39 (m, 2H), 4.23 (s, 3H); ¹³C NMR (126 MHz, Acetone-d₆) δ 156.4, 151.8, 150.6, 147.8, 146.5 (q, J_(CF)=2.3 Hz), 137.8, 124.2, 122.4, 121.5 (q, J_(CF)=255.2 Hz), 56.5; ¹⁹F NMR (376 MHz, Acetone-d₆) δ−58.78 (s, 3F); HRMS (ESI): Calc'd. for C₁₂H₉F₃N₅O₃+[M+H]⁺: 328.0652, Observed: 328.0667.

Example 157. Synthesis of N-(4-Butylphenyl)-6-methoxy-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-amine (1-157)

Compound 1-157 was synthesized by procedure 1-C using 1-138 to yield 1-157 in 66% as a yellow solid: ¹H NMR (400 MHz, Acetone-d₆) δ 9.47 (brs, 1H), 7.94-7.90 (m, 2H), 7.30-7.25 (m, 2H), 4.22 (s, 3H), 2.63 (t, 2H, J=7.6 Hz), 1.61 (q, 2H, J=7.8 Hz), 1.37 (h, 2H, J=7.8), 0.93 (t, 3H, J=7.3 Hz); ¹³C NMR (100 MHz, Acetone-d₆) δ 155.59, 151.08, 149.66, 146.61, 139.77, 135.44, 128.61, 121.65, 55.52, 34.78, 33.58, 22.05, 13.29; HRMS (ESI): Calc'd. for C₁₅H₁₈N₅O₂ ⁺[M+H]⁺: 300.1455, Observed: 300.1443.

Example 158. Synthesis of N-(-Fluoro-5-(trifluoromethyl)phenyl)-6-methoxy-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-amine (1-158)

Compound 1-158 was synthesized by procedure 1-C using 1-138 to yield 1-158 in 83% as a yellow solid: ¹H NMR (400 MHz, Acetone-d₆) δ 9.26 (brs, 1H), 8.64 (d, 1H, J=7.0 Hz), 7.74-7.68 (m, 1H), 7.61-7.53 (m, 1H), 4.30 (s, 3H); ¹³C NMR (100 MHz, Acetone-d₆) δ 157.93 (d, J=254 Hz), 156.26, 151.58, 150.85, 148.27, 127.34 (q, J=34 Hz), 127.08 (d, J=12 Hz), 125.17 (h, J=5 Hz), 124.76 (q, J=272 Hz), 123.37 (m, J=2 Hz), 117.70 (d, J=21 Hz), 56.91; ¹⁹F NMR (376 MHz, Acetone-d₆) δ−62.62 (s, 3F), −119.21-−119.31 (m, 1F); HRMS (ESI): Calc'd. for C₁₂H₈F₄N₅O₂ ⁺[M+H]⁺: 330.0609, Observed: 330.0611.

Example 159. Synthesis of N-(2-Fluorophenyl)-6-methoxy-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-amine (1-159)

Compound 1-159 was synthesized by procedure 1-C using 1-138 to yield 1-159 in 95% as a yellow solid: ¹H NMR (400 MHz, Acetone-d₆) δ 9.14 (brs, 1H), 8.26-8.18 (m, 1H), 7.38-7.26 (m, 3H), 4.29 (s, 3H); ¹³C NMR (100 MHz, Acetone-d₆) δ 156.44 (d, J=246 Hz), 156.11, 151.93, 150.88, 148.28, 128.10 (d, J=8 Hz), 126.31, 126.12 (d, J=11 Hz), 125.55 (d, J=4 Hz), 116.53 (d, J=20 Hz), 56.85; ¹⁹F NMR (376 MHz, Acetone-d₆) δ−125.90-−126.04 (m, 1F); HRMS (ESI): Calc'd. for C₁₁H₉FN₅O₂ ⁺[M+H]⁺: 262.0735, Observed: 262.0741.

Example 160. Synthesis of 6-Methoxy-N-(2-(trifluoromethyl)phenyl)-[1,2,5]oxadiazolo[3,4-B]pyrazin-5-amine (1-160)

Compound 1-160 was synthesized by procedure 1-C using 1-138 to yield 1-160 in 90% as a yellow solid: ¹H NMR (400 MHz, Acetone-d₆) δ 9.15 (brs, 1H), 8.14 (d, 1H, J=8.2 Hz), 7.89-7.78 (m, 1H), 7.60-7.53 (m, 1H), 4.31 (s, 3H); ¹³C NMR (100 MHz, Acetone-d₆) δ 156.34, 151.83, 150.85, 149.32, 135.75 (q, J=2 Hz), 134.27 (q, J=1 Hz), 129.33, 128.12, 127.60 (q, J=5 Hz), 125.39 (q, J=30 Hz), 124.86 (q, J=274 Hz), 56.97; ¹⁹F NMR (376 MHz, Acetone-d₆) δ−61.16 (s, 1F); HRMS (ESI): Calc'd. for C₁₂H₉F₃N₅O₂+[M+H]⁺: 312.0703, Observed: 312.0700.

Example 161. Synthesis of N-([1,1′-Biphenyl]-4-yl)-6-methoxy-[1,2,5]oxadiazolo[3,4-B]pyrazin-5-amine (1-161)

Compound 1-161 was synthesized by procedure 1-C using 1-138 to yield 1-161 in 70% as a yellow solid: ¹H NMR (400 MHz, Acetone-d₆) δ 9.63 (brs, 1H), 8.15 (d, 2H, J=8.6 Hz), 7.76 (d, 2H, J=8.6 Hz), 7.71 (d, 2H, J=7.6 Hz), 7.48 (t, 2H, J=7.5 Hz), 7.36 (t, 1H, J=7.3 Hz), 4.25 (s, 3H); ¹³C NMR (100 MHz, Acetone-d₆) δ HRMS (ESI): Calc'd. for C₁₇H₁₄N₅O₂ ⁺[M+H]+: 320.1142, Observed: 320.1127.

Example 162. Synthesis of N-(4-(tert-Butyl)phenyl)-6-methoxy-[1,2,5]oxadiazolo[3,4-B]pyrazin-5-amine (1-162)

Compound 1-162 was synthesized by procedure 1-C using 1-138 to yield 1-162 in 98% as a yellow solid: ¹H NMR (400 MHz, Acetone-d₆) δ 9.49 (brs, 1H), 7.95-7.90 (m, 2H), 7.50-7.45 (m, 2H), 4.21 (s, 3H), 1.33 (m, 9H); ¹³C NMR (100 MHz, Acetone-d₆) δ156.57, 152.06, 150.65, 148.91, 147.61, 136.18, 126.53, 122.40, 56.52, 35.14, 31.72. HRMS (ESI): Calc'd. for C₁₅H₁₈N₅O₂ ⁺[M+H]+: 300.1455, Observed: 300.1464.

Example 163. Synthesis of N-(2-Fluoro-4-(trifluoromethoxy)phenyl)-6-methoxy-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-amine (1-163)

Compound 1-163 was synthesized by procedure 1-C using 1-138 to yield 1-163 in 96% as a yellow solid: ¹H NMR (400 MHz, Acetone-d₆) δ 9.23 (brs, 1H), 8.30 (t, 1H J=8.8 Hz), 7.41 (dd, 1H, J=10.9 Hz), 7.35 (d, 1H, J=9.1 Hz), 4.29 (s, 3H); ¹³C NMR (100 MHz, Acetone-d₆) δ156.36, 156.16 (d, J=250 Hz), 151.77, 150.91, 148.36, 147.39 (dq, J=11 Hz), 127.61 (d, J=2 Hz), 125.43 (d, J=12 Hz), 121.41 (q, J=257 Hz), 118.21 (d, J=4 Hz), 110.64 (d, J=24 Hz), 56.86; ¹⁹F NMR (376 MHz, Acetone-d₆) δ−58.97 (s, 3F), −120.20 (t, 1F, J=9.8 Hz); HRMS (ESI): Calc'd. for C₁₂H₈F₄N₅O₃ ⁺[M+H]⁺: 346.0558, Observed: 346.0538.

Example 164. Synthesis Of N-(4-Isopropylphenyl)-6-methoxy-[1,2,5]oxadiazolo[3,4-B]pyrazin-5-amine (1-164)

Compound 1-164 was synthesized by procedure 1-C using 1-138 to yield 1-164 in 95% as a yellow solid: ¹H NMR (400 MHz, Acetone-d₆) δ 9.48 (brs, 1H), 7.95-7.90 (m, 2H), 7.35-7.30 (m, 2H), 4.22 (s, 3H), 2.94 (h, 1H, J=6.9 Hz), 1.25 (d, 6H, J=6.9 Hz); ¹³C NMR (100 MHz, Acetone-d₆) δ 156.61, 152.09, 150.67, 147.65, 146.77, 136.51, 127.60, 122.78, 56.52, 34.50, 24.40; HRMS (ESI): Calc'd. for C₁₄H₁₆N₅O₂ ⁺[M+H]⁺: 286.1299, Observed: 286.1299.

Example 165. Synthesis of 6-Methoxy-N-(4-(trifluoromethyl)phenyl)-[1,2,5]oxadiazolo[3,4-B]pyrazin-5-amine (1-165)

Compound 1-165 was synthesized by procedure 1-C using 1-138 to yield 1-165 in 79% as a yellow solid: ¹H NMR (400 MHz, Acetone-d₆) δ 9.82 (brs, 1H), 8.29 (d, 2H, J=8.8 Hz), 7.80 (d, 2H, J=8.8 Hz), 4.24 (s, 3H); ¹⁹F NMR (376 MHz, Acetone-d₆) δ −62.62 (s, 3F); ¹³C NMR (100 MHz, Acetone-d₆) δ HRMS (ESI): Calc'd. for C₁₂H₉F₃N₅O₂ ⁺[M+H]⁺: 312.0703, Observed: 312.0710.

Example 166. Synthesis of 6-Methoxy-N-(3-(trifluoromethyl)phenyl)-[1,2,5]oxadiazolo[3,4-B]pyrazin-5-amine (1-166)

Compound 1-166 was synthesized by procedure 1-C using 1-138 to yield 1-166 in 79% as a yellow solid: ¹H NMR (400 MHz, Acetone-d₆) δ 9.76 (brs, 1H), 8.43 (brs, 1H), 8.31 (d, 1H, J=8.4 Hz), 7.66 (t, 1H, J=8.1 Hz), 7.53 (d, 1H, J=8.1 Hz), 4.23 (s, 3H); ¹³C NMR (100 MHz, Acetone-d₆) δ 156.24, 151.51, 150.50, 147.69, 139.48, 131.35 (q, J=32 Hz), 130.72, 125.86 (q, J=1 Hz), 125.04 (q, J=272 Hz), 122.10 (q, J=4 Hz), 118.85 (q, J=4 Hz), 56.56; ¹⁹F NMR (376 MHz, Acetone-d₆) δ−63.19 (s, 3F); HRMS (ESI): Calc'd. for C₁₂H₉F₃N₅O₂ ⁺[M+H]⁺: 312.0703, Observed: 312.0696.

Example 167. Synthesis of 6-Methoxy-N-(4-pentylphenyl)-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-amine (1-167)

Compound 1-167 was synthesized by procedure 1-C using 1-138 to yield 1-167 in 45% as a yellow solid: ¹H NMR (400 MHz, Acetone-d₆) δ 9.40 (brs, 1H), 7.90 (d, 2H, J=8.6 Hz), 7.24 (d, 2H, J=8.6 Hz), 4.20 (s, 3H), 2.60 (t, 2H, J=7.8 Hz), 1.62 (q, 2H, J=7.7 Hz), 1.40-1.27 (m, 4H), 0.89 (t, 3H, J=6.9 Hz); ¹³C NMR (100 MHz, Acetone-d₆) δ156.44, 151.97, 150.55, 147.42, 140.71, 136.34, 129.52, 122.51, 56.49, 36.00, 32.25, 32.02, 23.24, 14.40; HRMS (ESI): Calc'd. for C₁₆H₂₀N₅O₂ ⁺[M+H]⁺: 314.1611, Observed: 314.1619.

Example 168. Synthesis of N-(4-(tert-Butyl)-2-fluorophenyl)-6-methoxy-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-amine (1-168)

Compound 1-168 was synthesized by procedure 1-C using 1-138 to yield 1-168 in 88% as a yellow solid: ¹H NMR (400 MHz, Acetone-d₆) δ 9.10 (brs, 1H), 8.20 (dd, 1H, J=7.5 Hz), 7.39-7.33 (m, 1H), 7.24-7.17 (m, 1H), 4.29 (s, 3H), 1.35 (s, 9H); ¹³C NMR (100 MHz, Acetone-d₆) δ 156.45, (d, J=244 Hz), 151.99, 150.87, 148.58 (d, J=4 Hz), 148.31, 125.03 (d, J=7 Hz), 123.56, 115.89 (d, J=20 Hz), 113.64 (d, J=20 Hz), 56.89, 35.39, 31.83; ¹⁹F NMR (376 MHz, Acetone-d₆) δ −129.53 (m, 1F); HRMS (ESI): Calc'd. for C₁₅H₁₇FN₅O₂+[M+H]⁺: 318.1361, Observed: 318.1353.

Example 169. Synthesis Of N-(4-Iodophenyl)-6-methoxy-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-amine (1-169)

Compound 1-169 was synthesized by procedure 1-C using 1-138 to yield 1-169 in 95% as a yellow solid: ¹H NMR (400 MHz, Acetone-d₆) δ 9.61 (brs, 1H), 7.91-7.87 (m, 2H), 7.82-7.78 (m, 2H), 4.22 (s, 3H); ¹³C NMR (100 MHz, Acetone-d₆) δ156.53, 151.84, 150.68, 147.72, 138.82, 124.63, 124.53, 89.12, 56.62; HRMS (ESI): Calc'd. for C₁₁H₉IN₅O₂ ⁺[M+H]⁺: 369.9795, Observed: 369.9810.

Example 170. Synthesis of N-(3-Iodophenyl)-6-methoxy-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-amine (1-170)

Compound 1-170 was synthesized by procedure 1-C using 1-138 to yield 1-170 in 94% as a yellow solid: ¹H NMR (400 MHz, Acetone-d₆) δ 9.57 (brs, 1H), 8.50 (s, 1H), 8.06 (d, 1H, J=8.3 Hz), 7.59 (d, 1H, J=7.9 Hz), 7.25 (t, 1H, J=8.1 Hz), 4.23 (s, 3H); ¹³C NMR (100 MHz, Acetone-d₆) δ 156.47, 151.78, 150.69, 147.74, 140.18, 134.83, 131.61, 131.08, 121.95, 94.28, 56.65; HRMS (ESI): Calc'd. for C₁₁H₉IN₅O₂ ⁺[M+H]⁺: 369.9795, Observed: 369.9782.

Example 171. Synthesis of N-(2-Iodo-4-(trifluoromethoxy)phenyl)-6-methoxy-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-amine (1-171)

Compound 1-171 was synthesized by procedure 1-C using 1-138 to yield 1-171 in 67% as a yellow solid: ¹H NMR (400 MHz, Acetone-d₆) δ 9.09 (brs, 1H), 8.39 (d, 1H, J=9.0 Hz), 7.96-7.93 (m, 1H), 7.58-7.53 (m, 1H), 4.33 (s, 3H); ¹³C NMR (100 MHz, Acetone-d₆) δ 156.19, 151.53, 150.66, 148.01, 146.95 (q, J=2 Hz), 138.65, 132.66, 126.22, 122.78, 121.28 (q, J=256 Hz), 94.34, 57.09; ¹⁹F NMR (376 MHz, Acetone-d₆) δ−58.78 (s, 3F); HRMS (ESI): Calc'd. for C₁₂H₈IF₃N₅O₃ ⁺[M+H]⁺: 453.9624, Observed: 453.9636.

Example 172. Synthesis of N-(2-Chloro-4-(trifluoromethoxy)phenyl)-6-methoxy-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-amine (1-172)

Compound 1-172 was synthesized by procedure 1-C using 1-138 to yield 1-172 in 98% as a yellow solid: ¹H NMR (400 MHz, Acetone-d₆) δ 9.07 (brs, 1H), 8.59 (d, 1H, J=9.1 Hz), 7.61-7.59 (m, 1H), 7.48 (d, 1H, J=9.1 Hz), 4.32 (s, 3H); ¹³C NMR (100 MHz, Acetone-d₆) δ 156.00, 151.33, 150.53, 147.53, 146.60 (q, J=2 Hz), 134.08, 127.66, 125.96, 123.32, 121.49, 121.24 (q, J=256 Hz), 57.10; ¹⁹F NMR (376 MHz, Acetone-d₆) δ−58.87 (s, 3F); HRMS (ESI): Calc'd. for C₁₂H₈F₃ClN₅O₃ ⁺[M+H]⁺: 362.0268, Observed: 362.0265.

Example 173. Synthesis of N-(3-Chloro-4-(trifluoromethoxy)phenyl)-6-methoxy-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-amine (1-173)

Compound 1-173 was synthesized by procedure 1-C using 1-138 to yield 1-173 in 85% as a yellow solid: ¹H NMR (400 MHz, Acetone-d₆) δ 9.68 (brs, 1H), 8.37 (d, 1H, J=2.6 Hz), 8.02 (dd, 1H, J=9.0 Hz), 7.50 (dq, 1H, J=9.0 Hz), 4.20 (s, 3H); ¹³C NMR (100 MHz, Acetone-d₆) δ 155.81, 151.08, 150.18, 147.14, 141.74 (q, J=2 Hz), 138.42, 127.50, 123.84, 123.69, 121.84, 121.21 (q, J=256 Hz), 56.43; ¹⁹F NMR (376 MHz, Acetone-d₆) δ−58.79 (s, 3F); HRMS (ESI): Calc'd. for C₁₂H₈F₃ClN₅O₃ ⁺[M+H]⁺: 362.0268, Observed: 362.0265.

Example 174. Synthesis of N-(3-Bromo-4-(trifluoromethoxy)phenyl)-6-methoxy-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-amine (1-174)

Compound 1-174 was synthesized by procedure 1-C using 1-138 to yield 1-174 in 97% as a yellow solid: ¹H NMR (400 MHz, Acetone-d₆) δ 9.67 (brs, 1H), 8.50 (d, 1H, J=2.6 Hz), 8.08 (dd, 1H, J=9.0 Hz), 7.49 (dq, 1H, J=9.0 Hz), 4.20 (s, 3H); ¹³C NMR (100 MHz, Acetone-d₆) δ155.85, 151.13, 150.22, 147.17, 143.16 (q, J=2 Hz), 138.51, 126.79, 123.45, 122.56, 121.22 (q, J=257 Hz), 116.21, 56.47; ¹⁹F NMR (376 MHz, Acetone-d₆) δ−58.43 (s, 3F); HRMS (ESI): Calc'd. for C₁₂H₈F₃BrN₅O₃ ⁺[M+H]⁺: 405.9763, Observed: 405.9763.

Example 175. Synthesis of 6-Methoxy-N-(2-methoxy-4-(trifluoromethoxy)phenyl)-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-amine (1-175)

Compound 1-175 was synthesized by procedure 1-C using 1-138 to yield 1-175 in 73% as a yellow solid: ¹H NMR (400 MHz, Acetone-d₆) δ 9.50 (brs, 1H), 8.83 (d, 1H, J=9.0 Hz), 7.15 (s, 1H), 7.09 (d, 1H, J=9.0 Hz), 4.10 (s, 3H), 3.67 (s, 3H); ¹⁹F NMR (376 MHz, Acetone-d₆) δ−58.72 (s, 3F); HRMS (ESI): Calc'd. for C₁₃H₁₁F₃N₅O₄ ⁺[M+H]⁺: 358.0763, Observed: 358.0756.

Example 176. Synthesis Of N-(4′-Fluoro-[1,1′-biphenyl]-4-yl)-6-methoxy-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-amine (1-176)

In a screw-cap vial, a solution of 4′-fluoro-[1,1′-biphenyl]-4-amine (0.100 g, 0.534 mmol) in anhydrous THF (1 mL) was added to a stirring mixture of 1-138 (0.100 g, 0.536 mmol) in anhydrous THF (1 mL). Then, to the brown mixture, Et₃N (0.09 mL, 0.6 mmol) was added and the resulting dark mixture was stirred at room temperature for 20 h. The mixture was diluted with EtOAc, washed with brine, dried (Na₂SO₄), and concentrated to a yellow solid. The solid was purified by chromatography on SiO₂ (gradient: 40-60% EtOAc/hexanes) to yield a yellow solid. The solid was dissolved in minimal amount of acetone and precipitation was induced by the addition of hexanes. The precipitate was filtered, washed with hexanes, and collected to yield 1-176 (66%) as a bright yellow solid: ¹H NMR ((CD₃)₂CO, 500 MHz) δ 9.63 (s, 1H), 8.16-8.13 (m, 2H), 7.76-7.72 (m, 4H), 7.26-7.22 (m, 2H), 4.24 (s, 3H); ¹⁹F NMR ((CD₃)₂CO, 376 MHz) δ−117.27-−117.35 (m, 1F); ¹³C NMR ((CD₃)₂CO, 125 MHz) δ 163.3 (d, J_(CF)=244.7 Hz), 156.5, 151.9, 150.6, 147.6, 138.1, 137.5 (d, J_(CF)=3.2 Hz), 137.4, 129.4 (d, J_(CF)=8.1 Hz), 128.0, 122.9, 116.5 (d, J_(CF)=21.7 Hz), 56.5; HRMS (ES⁺) m/z calc'd. for C₁₇H₁₃FN₅O₂ (M+H)⁺338.1048, found 338.1068.

Example 177. Synthesis of 6-Methoxy-N-methyl-N-(4-(trifluoromethyl)phenyl)-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-amine (1-177)

Compound 1-177 was synthesized by procedure 1-C using 1-138 to yield 1-177 in 72% as a yellow solid: ¹H NMR (400 MHz, Acetone-d₆) δ 7.81 (d, 2H, J=8.3 Hz), 7.62 (d, 2H, J=8.3 Hz), 3.72 (s, 3H), 3.63 (s, 3H); ¹⁹F NMR (376 MHz, Acetone-d₆) δ−62.74 (s, 3F); HRMS (ESI): Calc'd. for C₁₃H₁₁F₃N₅O₂ ⁺[M+H]⁺: 326.0859, Observed: 326.0845.

Example 178. Synthesis of N-(3-Fluoro-4-(trifluoromethyl)phenyl)-6-methoxy-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-amine (1-178)

Compound 1-178 was synthesized by procedure 1-C using 1-138 to yield 1-178 in 84% as a yellow solid: ¹H NMR (400 MHz, Acetone-d₆) δ 9.91 (s, 1H), 8.36-8.13 (m, 1H), 8.05-7.89 (m, 1H), 7.84-7.70 (m, 1H), 4.23 (s, 3H). ¹⁹F NMR (376 MHz, Acetone-d₆) δ−61.28 (d, J=12.3 Hz), 114.52 (td, J=12.7, 8.2 Hz). ¹³C NMR (101 MHz, Acetone-d₆) δ 160.48 (dq, J=252.0, 2.4 Hz), 156.12, 151.25, 150.48, 147.65, 144.43-144.20 (m), 128.63-128.38 (m), 123.75 (dd, J=269.7, 1.1 Hz), 117.61 (d, J=3.5 Hz), 114.45-113.26 (m), 109.89 (d, J=26.4 Hz), 56.67; HRMS (ESI⁺): Calc'd. for (C₁₂H₈F₄N₅O₂+)+[M+H]−: 330.0609 Found: 330.0624.

Example 179. Synthesis of 5-butoxy-6-chloro-[1,2,5]oxadiazolo[3,4-b]pyrazine (1-179)

5,6-dichloro-[1,2,5]oxadiazolo[3,4-b]pyrazine (1.00 g) was dissolved in Dry THF (10 mL) and TEA (0.73 mL 1 equiv.) was added. The solution was mixed and 1-Butanol (0.9 equiv.) was added dropwise over a few minutes. The solution evolved into a slurry and was allowed to stir at room temperature for 30 mins. The solvent was then removed under reduced pressure and purified via Silica to produce 5-butoxy-6-chloro-[1,2,5]oxadiazolo[3,4-b]pyrazine (1-179) 879 mg (74% yield) as an orange liquid. ¹H NMR (400 MHz, Acetone-d₆) δ 4.66 (t, J=6.4 Hz, 2H), 2.00-1.81 (m, 2H), 1.66-1.49 (m, 2H), 1.06-0.97 (m, 3H). ¹³C NMR (101 MHz, Acetone-d₆) δ158.11, 153.29, 152.09, 151.32, 71.16, 30.80, 19.73, 13.92.

Example 180. Synthesis of 6-Butoxy-N-(2-fluorophenyl)-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-amine (1-180)

Compound 1-180 was synthesized by procedure 1-C using 1-179 to yield 1-180 in 57% as a yellow solid: ¹H NMR (400 MHz, Acetone-d₆) δ 9.02 (s, 1H), 8.32-8.20 (m, 1H), 7.39-7.24 (m, 3H), 4.73-4.65 (m, 2H), 2.00-1.88 (m, 2H), 1.66-1.52 (m, 2H), 1.08-0.96 (m, 3H)). ¹⁹F NMR (376 MHz, Acetone-d₆) δ−126.31-−126.69 (m, 1F); ¹³C NMR (101 MHz, Acetone-d₆) δ155.80 (d, J=246.4 Hz), 155.76, 151.62, 150.72, 148.04, 127.82 (d, J=7.8 Hz), 126.04 (d, J=11.0 Hz), 125.85, 125.44 (d, J=3.8 Hz), 116.30 (d, J=19.5 Hz), 70.48, 30.90, 19.74, 14.00; HRMS (ESI⁺) m/z calc'd. for C₁₄H₁₅FN₅O₂ [M+H]⁺ 304.1204, found 304.1211.

Example 181. Synthesis of 6-Butoxy-N-(4-(trifluoromethoxy)phenyl)-[1,2,5]oxadiazolo[3,4-B]pyrazin-5-amine (1-181)

Compound 1-181 was synthesized by procedure 1-C using 1-179 to yield 1-181 in 63% as an off-white solid:¹H NMR (400 MHz, Acetone-d₆) δ 9.70-9.52 (m, 1H), 8.19-8.02 (m, 2H), 7.56-7.35 (m, 2H), 4.67 (t, J=6.7 Hz, 2H), 1.97-1.84 (m, 2H), 1.61-1.48 (m, 2H), 0.99 (t, J=7.4 Hz, 3H); ¹⁹F NMR (376 MHz, Acetone-d₆) δ−58.78 (s, 3F); ¹³C NMR (101 MHz, Acetone-d₆) δ 155.93, 151.58, 150.64, 147.80, 146.45 (q, J_(CF)=1.9 Hz), 137.63, 124.41, 122.37, 121.44f (q, J_(CF)=255.4 Hz), 70.40, 30.88, 19.68, 14.02; HRMS (ESI⁺) m/z calc'd. for C₁₅H₁₅F₃N₅O₃ [M+H]⁺ 370.1122, found 370.1129.

Example 182. Synthesis of 6-(2,2,2-Trifluoroethoxy)-N-(4-(trifluoromethoxy)phenyl)-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-amine (1-182)

5,6-dichloro-[1,2,5]oxadiazolo[3,4-b]pyrazine (150 mg) was dissolved in Dry THF (5 mL) and TEA (0.12 mL 1.1 equiv.) was added. The solution was mixed and 2,2,2-trifluoroethanol (1.1 equiv.) was added dropwise over a few minutes. The solution evolved into a slurry and was allowed to stir at room temperature for 30 mins. 4-(trifluoromethoxy)aniline (0.9 equiv.) was then added and the reaction was allowed to stir at room temperature for 16 h. The solvent was then removed under reduced pressure and purified via Silica to yield the title compound 1-182 (62 mg 20%) as an orange oil: ¹H NMR (500 MHz, Acetone-d₆) δ 9.88 (s, 1H), 8.17-7.96 (m, 2H), 7.62-7.20 (m, 2H), 1.96 (s, 2H); ¹⁹F NMR (376 MHz, Acetone-d₆) δ−58.78 (s, 3F), −73.35 (s, 3F); ¹³C NMR (126 MHz, Acetone-d₆) δ153.82, 151.07, 149.12, 146.48, 145.86 (d, J=2.2 Hz), 136.45, 124.09, 123.10 (q, 277.5 Hz), 121.47, 120.75 (d, J=260.5 Hz), 64.96-63.13 (m); HRMS (ESI⁺) m/z calc'd. for C₁₃H₈F₆N₅O₃ [M+H]+ 396.0526, found 396.0543.

Example 183. Synthesis of 6-Isopropoxy-N-(4-(trifluoromethyl)phenyl)-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-amine (1-183) Step 1. Synthesis of 5-Chloro-6-isopropoxy-[1,2,5]oxadiazolo[3,4-b]pyrazine (1-183-int))

In a 25 ml round bottom flask, 5,6-dichloro-[1,2,5]oxadiazolo[3,4-b]pyrazine (1-2) (0.403 g, 2.11 mmol) and Et₃N (0.214 g, 2.11 mmol) were dissolved in 10 mL of anhydrous THF. Isopropanol (0.127 g, 2.11 mmol) was added. The mixture was heated to 45° C. and stirred for 16 h. The mixture was concentrated and purified chromatography on SiO₂ to obtain 1-183-int (19%) as a yellow solid: ¹H NMR (400 MHz, Acetone-d₆) δ 5.58 (h, J=6.2 Hz, 1H), 1.53 (d, J=6.2 Hz, 6H); ¹³C NMR (100 MHz, Acetone-d₆) δ 157.58, 153.76, 152.27, 151.35, 76.09, 21.66.

Step 2. Synthesis of 6-Isopropoxy-N-(4-(trifluoromethyl)phenyl)-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-amine (1-183)

In a screw-cap vial, 1-183-int (0.088 g, 0.410 mmol) was dissolved in 3 mL of anhydrous THF, and 4-(trifluoromethyl)aniline (0.145 g, 0.902 mmol) was added. The mixture was heated to reflux and stirred for 16 h. The next day, the mixture was concentrated and purified by chromatography on SiO₂ to obtain 1-183 (83%) as a yellow solid: ¹H NMR (400 MHz, Acetone-d₆) δ 9.65 (brs, 1H), 8.21 (d, 2H, J=8.5 Hz), 7.78 (d, 2H, J=8.5 Hz), 5.68 (h, 1H, J=6.2 Hz), 1.52 (d, 6H, J=6.2 Hz); ¹³C NMR (100 MHz, Acetone-d₆) δ 155.34, 151.48, 150.82, 148.17, 142.30, 126.98 (q, J=3.9 Hz), 126.88 (q, J=32.4 Hz), 125.45 (q, J=272.6 Hz), 122.82, 75.30, 21.76; ¹⁹F NMR (376 MHz, Acetone-d₆) δ−62.61 (s, 3F); HRMS (ESI): Calc'd. for C₁₄H₉F₆IN₅O₂ ⁺[M+H]⁺: 519.9705, Observed: 519.9714.

Example 184. Synthesis of 6-(2-Fluorophenoxy)-N-(4-(trifluoromethyl)phenyl)-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-amine (1-184)

In a screw-cap vial, 1-2 (0.300 g, 1.57 mmol) was dissolved in 8 mL of anhydrous THF at 0° C. In a separate vial, 2-fluorophenol (0.166 g, 1.73 mmol) and sodium tert-butoxide (0.194 g, 1.73 mmol) were mixed in 2 mL of anhydrous THF at 0° C. This mixture was added dropwise to the initial vial while stirring. This was followed by the addition of 4-(trifluoromethyl)aniline (0.506 g, 3.14 mmol). The mixture was refluxed and stirred for 16 h. The next day, the mixture was concentrated and purified chromatography on SiO₂ to obtain 1-184 (18%) as a yellow solid: ¹H NMR (400 MHz, Acetone-d₆) δ 10.21 (brs, 1H), 8.38 (d, 2H, J=8.4 Hz), 7.84 (d, 2H, J=8.4 Hz), 7.56 (td, 1H, J=7.8, 1.6 Hz), 7.53-7.36 (m, 3H); ¹⁹F NMR (376 MHz, Acetone-d₆) δ−62.57 (s, 3F), −129.41-−129.49 (m, 1F); HRMS (ESI): Calc'd. for C₁₄H₉F₆IN₅O₂ ⁺[M+H]⁺: 519.9705, Observed: 519.9714.

Example 185. Synthesis of 6-(4-(Trifluoromethyl)phenoxy)-N-(4-(trifluoromethyl)phenyl)-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-amine (1-185)

In a screw-cap vial, 1-2 (0.150 g, 0.785 mmol) was dissolved in 3 mL of anhydrous THF at 0° C. In a separate vial, 4-(trifluoromethyl)phenol (0.127 g, 0.785 mmol) and sodium tert-butoxide (0.076 g, 0.785 mmol) were mixed in 2 mL of anhydrous THF at 0° C. This mixture was added dropwise to the initial vial while stirring. This was followed by the addition of 4-(trifluoromethyl)aniline (0.506 g, 3.14 mmol). The mixture was refluxed and stirred for 16 h. The next day, the mixture was concentrated and purified by chromatography on SiO₂ to obtain 1-185 (45%) as a yellow solid: ¹H NMR (400 MHz, Acetone-d₆) δ 10.20 (brs, 1H), 8.36 (d, 2H, J=8.4 Hz), 7.97 (d, 2H, J=8.4 Hz), 7.84 (d, 2H, J=8.5 Hz), 7.73 (d, 2H, J=8.5 Hz); ¹⁹F NMR (376 MHz, Acetone-d₆) δ−62.62 (s, 3F), −62.72 (s, 3F); HRMS (ESI): Calc'd. for C₁₈H₁₀F₆N₅O₂ ⁺[M+H]⁺: 442.0733, Observed: 442.0726.

Example 186. Synthesis of 6-Phenoxy-N-(4-(trifluoromethyl)phenyl)-[1,2,5]oxadiazolo[3,4-B]pyrazin-5-amine (1-186)

In a screw-cap vial, 1-2 (0.300 g, 1.57 mmol) was dissolved in 5 mL of anhydrous THF at 0° C. In a separate vial, 4-(trifluoromethyl)phenol (0.140 g, 1.49 mmol) and sodium tert-butoxide (0.143 g, 1.49 mmol) were mixed in 3 mL of anhydrous THF at 0° C. This mixture was added dropwise to the initial vial while stirring. This was followed by the addition of 4-(trifluoromethyl)aniline (0.607 g, 3.78 mmol). The mixture was refluxed and stirred for 16 h. The next day, the mixture was concentrated and purified by chromatography on SiO₂ to obtain 1-186 (21%) as a yellow solid: ¹H NMR (400 MHz, Acetone-d₆) δ 10.15 (brs, 1H), 8.38 (d, 2H, J=8.4 Hz), 7.84 (d, 2H, J=8.5 Hz), 7.62-7.54 (m, 2H), 7.47-7.39 (m, 3H); ¹³C NMR (100 MHz, Acetone-d₆) δ 156.08, 152.46, 151.78, 150.33, 147.99, 142.37 (q, J=1.2 Hz), 130.79, 127.75, 126.99 (q, J=3.9 Hz), 126.83 (q, J=32.6 Hz), 125.34 (q, J=270.5 Hz), 122.71, 122.54; ¹⁹F NMR (376 MHz, Acetone-d₆) δ−62.62 (s, 3F); HRMS (ESI): Calc'd. for C₁₇H₁₁F₃N₅O₂ ⁺[M+H]⁺: 374.0859, Observed: 374.0857.

Example 187. Synthesis of N-(2-Fluorophenyl)-6-(2,2,2-trifluoroethoxy)-[1,2,5]oxadiazolo[3,4-B ]pyrazin-5-amine (1-187)

A round-bottom flask containing 1-2 (0.21 g, 1.1 mmol) was evacuated and flushed with N₂ (3×). Then, under an atmosphere of N₂, the solid was cooled in an ice bath and diluted sequentially with dry THF (3 mL), 2-fluoroaniline (0.10 mL, 1.0 mmol), and Et₃N (0.15 mL, 1.1 mmol). The resulting red solution, cooled in an ice bath, was stirred for 2.5 h, filtered to remove the salts rinsing with EtOAc, concentrated to remove the solvents, passed through a SiO₂ plug (CH₂Cl₂), and concentrated to a crude yellow/orange solid (0.179 g). The crude solid (0.179 g) in a round-bottom flask was evacuated and refilled with N₂ (3×). Then, the solid was diluted sequentially with anhydrous THF (3 mL), 2,2,2-trifluoroethanol (0.15 mL, 2.1 mmol), and Et₃N (0.15 mL, 1.1 mmol). The resulting mixture was stirred at rt under an atmosphere of N₂ for 17 h, filtered to remove the salts rinsing with EtOAc, and concentrated to a red solid. The solid was purified by chromatography on SiO₂ (gradient: 10-15% EtOAc/hexanes) to yield 1-187 (34%) as a light yellow solid: ¹H NMR ((CD₃)₂CO, 500 MHz) δ 9.31 (s, 1H), 8.08 (t, J=7.8 Hz, 1H), 7.38-7.30 (m, 3H), 5.32 (q, J=8.5 Hz, 2H); ¹³C NMR ((CD₃)₂CO, 125 MHz) δ 156.5 (d, J_(CF)=247 Hz), 154.5, 152.1, 150.2, 147.8, 128.6 (d, J_(CF)=8.0 Hz), 126.9, 125.8 (d, J_(CF)=11.4 Hz), 125.5 (d, J_(CF)=3.8 Hz), 124.1 (q, J_(CF)=277 Hz), 116.6 (d, J_(CF)=19.6 Hz), 65.12 (q, J_(CF)=37.1 Hz). ¹⁹F NMR ((CD₃)₂CO, 376 MHz) δ−73.7 (t, J=8.5 Hz, 3 F), −124.6 to −124.7 (m, 1 F); HRMS (ESI⁻) m/z calc'd. for C₁₂H₆F₄N₅O₂ (M−H)⁻328.0463, found 328.0492.

Example 188. Synthesis of 3-((6-((4-(Trifluoromethoxy)phenyl)amino)-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-yl)oxy)propan-1-ol (1-188)

A round-bottom flask containing 1-2 (0.200 g, 1.05 mmol) was evacuated and refilled with N₂ (3×). Then, the flask was placed in an ice bath and the solid was diluted sequentially with anhydrous THF (3 mL), 4-(trifluoromethoxy)aniline (0.13 mL, 0.97 mmol), and Et₃N (0.15 mL, 1.1 mmol). The resulting mixture was stirred at 0° C. under N₂ for 2 h and then allowed to warm to room temperature, diluted with 1,3-propanediol (1.40 mL, 19.5 mmol) and Et₃N (0.15 mL, 1.1 mmol), and stirred for an additional 4.5 h. The mixture was diluted with EtOAc, washed with brine, dried (Na₂SO₄), and concentrated to a red oil. The oil was purified by chromatography on SiO₂ (gradient: 70-80% EtOAc/hex) to yield 1-188 (36%) as a yellow solid: ¹H NMR ((CD₃)₂CO, 400 MHz) δ 9.68 (br s, 1H), 8.12-8.08 (m, 2H), 7.44-7.40 (m, 2H), 4.79 (t, J=6.4 Hz, 2H), 3.88-3.78 (m, 3H), 2.16-2.09 (m, 2H); ¹⁹F NMR ((CD₃)₂CO, 376 MHz) δ−58.8 (s, 3 F); ¹³C NMR ((CD₃)₂CO, 125 MHz) δ 156.0, 151.7, 150.7, 147.9, 146.5 (q, J_(CF)=2.1 Hz), 137.7, 124.3, 122.4, 121.5 (q, J_(CF)=255 Hz), 68.4, 59.2, 32.1; HRMS (ESI⁺) m/z calc'd. for C₁₄H₁₃F₃N₅O₄ (M+H)⁺372.0914, found 372.0908.

Example 189. Synthesis of 2-Methyl-3-((6-((4-(trifluoromethoxy)phenyl)amino)-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-yl)oxy)propan-1-ol (1-189)

A round-bottom flask containing 1-2 (0.200 g, 1.05 mmol) was evacuated and refilled with N₂ (3×). Then, the flask was placed in an ice bath and the solid was diluted sequentially with anhydrous THF (3 mL), 4-(trifluoromethoxy)aniline (0.13 mL, 0.97 mmol), and Et₃N (0.15 mL, 1.1 mmol). The resulting mixture, cooled in an ice bath, was stirred under N₂ for 2 h and then allowed to warm to room temperature, diluted with 2-methyl-1,3-propanediol (1.70 mL, 19.1 mmol) and Et₃N (0.15 mL, 1.1 mmol), and stirred for an additional 4.5 h. The mixture was diluted with EtOAc, washed with brine, dried (Na₂SO₄), and concentrated to a red oil. The oil was purified by chromatography on SiO₂ (gradient: 1-5% MeOH/CH₂Cl₂) to yield 1-189 (88%) as a viscous yellow oil: ¹H NMR ((CD₃)₂CO, 400 MHz) δ 9.61 (bs, 1H), 8.10-8.06 (m, 2H), 7.45-7.40 (m, 2H), 4.68 (dd, J=10.7, 6.7 Hz, 1H), 4.59 (dd, J=10.7, 6.4 Hz, 1H), 3.93 (t, J=5.3 Hz, 1H), 3.74-3.63 (m, 2H), 2.37-2.28 (m, 1H), 1.09 (d, J=6.9 Hz, 3H); ¹⁹F NMR ((CD₃)₂CO, 376 MHz) δ−58.8 (s, 3 F); ¹³C NMR ((CD₃)₂CO, 125 MHz) δ 156.1, 151.6, 150.7, 147.9, 146.6 (q, J_(CF)=2.1 Hz), 137.6, 124.4, 122.4, 121.5 (q, J_(CF)=255 Hz), 73.2, 64.8, 35.9, 14.0; HRMS (ESI⁺) m/z calc'd. for C₁₅H₁₅F₃N₅O₄ (M+H)⁺386.1071, found 386.1064.

Example 190. Synthesis of 1-((6-((4′-Fluoro-[1,1′-biphenyl]-4-yl)amino)-[1,2,5]oxadiazolo[3,4-B]pyrazin-5-yl)oxy)propan-2-one (1-190)

In a screw-cap vial, 4′-fluoro-[1,1′-biphenyl]-4-amine (0.175 g, 0.935 mmol) was added quickly to a stirring mixture of 1-2 (0.200 g, 1.05 mmol) in THF (4 mL). To the brown mixture, Et₃N (0.15 mL, 1.1 mmol) was added. The resulting reddish brown mixture was stirred at room temperature for 3 h. Then, a mixture of 1-hydroxypropan-2-one (0.150 g, 2.02 mmol) and Et₃N (0.15 mL, 1.1 mmol) in THF (2 mL) was added and stirring was continued for 21 h. The mixture was diluted with EtOAc, washed with brine, dried (Na₂SO₄), and concentrated to a brownish yellow solid. The solid was purified by chromatography on SiO₂ (gradient: 30-60% EtOAc/hexanes) to yield 1-190 (42%) as a yellow solid: ¹H NMR ((CD₃)₂CO, 500 MHz) δ 9.74 (s, 1H), 8.16-8.13 (m, 2H), 7.76-7.73 (m, 4H), 7.26-7.23 (m, 2H), 5.41 (s, 2H), 2.31 (s, 3H); ¹⁹F NMR ((CD₃)₂CO, 376 MHz) δ−117.25-−117.32 (m, 1F); ¹³C NMR ((CD₃)₂CO, 125 MHz) δ 200.4, 163.4 (d, J_(CF)=244.7 Hz), 155.2, 152.0, 150.2, 147.3, 138.0, 137.54, 137.45 (d, J_(CF)=3.2 Hz), 129.5 (d, J_(CF)=8.1 Hz), 128.1, 123.0, 116.5 (d, J_(CF)=21.4 Hz), 72.6, 26.1; HRMS (ES⁻) m/z calc'd. for C₁₉H₁₃FN₅O₃ (M−H)⁻378.1008, found 378.1010.

Example 191. Synthesis of 3-((6-((4′-Fluoro-[1,1′-biphenyl]-4-yl)amino)-[1,2,5]oxadiazolo[3,4-B]pyrazin-5-yl)oxy)propane-1,2-diol (1-191)

In a screw-cap vial, 4′-fluoro-[1,1′-biphenyl]-4-amine (0.175 g, 0.935 mmol) was added quickly to a stirring mixture of 1-2 (0.200 g, 1.05 mmol) in THF (4 mL). To the brown mixture, Et₃N (0.15 mL, 1.1 mmol) was added. The resulting reddish brown mixture was stirred at room temperature for 3 h. Then, a mixture of propane-1,2,3-triol (1.75 g, 19.0 mmol) and Et₃N (0.15 mL, 1.1 mmol) in THF (2 mL) was added and stirring was continued for 21 h. The mixture was diluted with EtOAc, washed with brine, dried (Na₂SO₄), and concentrated to a brownish yellow solid. The solid was purified by chromatography on SiO₂ (gradient: 0-4% MeOH/CH₂Cl₂) to yield 1-191 (26%) as a yellow solid: 1H NMR ((CD₃)₂CO, 500 MHz) δ 9.54 (s, 1H), 8.09-8.06 (m, 2H), 7.76-7.72 (m, 4H), 7.26-7.22 (m, 2H), 4.80 (dd, J=11.1, 3.8 Hz, 1H), 4.66 (dd, J=11.1, 6.9 Hz, 1H), 4.47 (br s, 1H), 4.25-4.17 (m, 1H), 4.09-3.94 (m, 1H), 3.81-3.72 (m, 2H); ¹⁹F NMR ((CD₃)₂CO, 376 MHz) δ−117.25-−117.32 (m, 1F); 13C NMR ((CD₃)₂CO, 125 MHz) δ 163.3 (d, J_(CF)=244.8 Hz), 156.1, 151.8, 150.6, 147.6, 137.9, 137.5, 137.4 (d, J_(CF)=3.1 Hz), 129.4 (d, J_(CF)=8.1 Hz), 128.0, 123.2, 116.5 (d, J_(CF)=21.5 Hz), 72.5, 70.2, 63.9; HRMS (ES⁻) m/z calc'd. for C₁₉H₁₅FN₅O₄ (M−H)⁻ 396.1114, found 396.1114.

Example 192. Synthesis of N-(6-Methoxy-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-yl)-4-(Ttrifluoromethyl)benzamide (1-192)

Compound 1-192 was synthesized by procedure 1-D using 1-138 to yield 1-192 in 27% as a colorless solid: ¹H NMR (400 MHz, Acetone-d₆) δ 10.33 (s, 1H), 8.29-8.12 (m, 2H), 8.07-7.82 (m, 2H), 4.26 (s, 3H); ¹⁹F NMR (376 MHz, Acetone-d₆) δ−63.59 (s, 3F); HRMS (ESI⁺) m/z calc'd. for C₁₃H₉F₃N₅O₃ [M+H]⁺ 340.0652, found 340.0672.

Example 193. Synthesis of N-(6-Butoxy-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-yl)-2-fluorobenzamide (1-193)

Compound 1-193 was synthesized by procedure 1-D using 1-179 to yield 1-193 in 32% as a colorless solid: ¹H NMR (400 MHz, Acetone-d₆) δ 10.30 (s, 1H), 8.06 (td, J=7.8, 1.9 Hz, 1H), 7.81-7.71 (m, 1H), 7.53-7.35 (m, 2H), 4.71 (t, J=6.5 Hz, 2H), 2.01-1.89 (m, 2H), 1.69-1.49 (m, 2H), 1.02 (t, J=7.4 Hz, 3H); ¹⁹F NMR (376 MHz, Acetone-d₆) δ−114.17-−114.32 (m, 1F); ¹³C NMR (126 MHz, Acetone-d₆) δ 161.34 (d, J=247.9 Hz), 160.97 (d, J=3.2 Hz), 155.68, 151.35, 150.81, 146.74, 136.13 (d, J=9.7 Hz), 132.74 (d, J=2.0 Hz), 126.30 (d, J=3.7 Hz), 121.99 (d, J=11.8 Hz), 117.40 (d, J=24.3 Hz), 70.82, 30.89, 19.64, 13.95; HRMS (ESI⁺) m/z calc'd. for C₁₅H₁₅FN₅O₃ [M+H]⁺ 332.1153, found 332.1149.

Example 194. Synthesis of N-(6-Butoxy-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-yl)-2,4-difluorobenzamide (1-194)

Compound 1-194 was synthesized by procedure 1-D using 1-179 to yield 1-194 in 26% as a colorless solid: ¹H NMR (400 MHz, Acetone-d₆) δ 10.26 (s, 1H), 8.19-8.07 (m, 1H), 7.38-7.25 (m, 2H), 4.70 (t, J=6.5 Hz, 2H), 2.00-1.87 (m, 2H), 1.70-1.47 (m, 2H), 1.01 (t, J=7.4 Hz, 3H); ¹⁹F NMR (376 MHz, Acetone-d₆) δ−103.37-−103.81 (m, 1F), −109.13-−109.65 (m, 1F); HRMS (ESI⁺) m/z calc'd. for C₁₅H₁₄F₂N₅O₃ [M+H]+ 350.1059, found 350.1071.

Example 195. Synthesis of (3R,5R,7R)-N-(6-Butoxy-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-yl)adamantane-1-carboxamide (1-195)

Compound 1-195 was synthesized by procedure 1-D using 1-179 to yield 1-195 in 57% as a colorless solid: ¹H NMR (500 MHz, Chloroform-d) δ 8.89 (s, 1H), 4.67 (t, J=6.6 Hz, 2H), 2.14 (q, J=3.1 Hz, 3H), 2.00-1.89 (m, 8H), 1.86-1.68 (m, 7H), 1.61-1.49 (m, 2H), 1.05 (t, J=7.4 Hz, 3H); ¹³C NMR (126 MHz, Chloroform-d) δ 174.35, 153.64, 149.93, 149.14, 144.53, 70.50, 43.11, 39.11, 38.76, 36.53, 36.30, 30.29, 28.00, 19.32, 13.83; HRMS (ESI⁺) m/z calc'd. for C₁₉H₂₆N₅O₃ [M+H]⁺ 372.2030, found 372.2017.

Example 196. Synthesis of N-(6-(Benzyloxy)-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-yl)-4-(trifluoromethyl)benzamide (1-196) Step 1. Synthesis of 5-(benzyloxy)-6-chloro-[1,2,5]oxadiazolo[3,4-b]pyrazine (1-196 int)

5,6-dichloro-[1,2,5]oxadiazolo[3,4-b]pyrazine (750 mg) was dissolved in Dry THF (40 mL) and TEA (0.600 mL 1.1 equiv.) was added the solution was cooled to 0 C. The solution was mixed and benzyl alcohol (0.9 equiv.) was added dropwise over a few minutes. The mixture was stirred at 0 C for 1 h, then 30 minutes at room temperature. The solvent was then removed under reduced pressure and purified via Silica to yield the title compound 1-196 int. (400 mg 39%) as white solid: ¹H NMR (400 MHz, Acetone-d₆) δ 7.64-7.58 (m, 2H), 7.53-7.36 (m, 3H), 5.71 (s, 2H).

Step 2. Synthesis of N-(6-(Benzyloxy)-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-yl)-4-(trifluoromethyl)benzamide (1-196)

Compound 1-197 was synthesized by procedure 1-D using 1-179 to yield 1-196 in 63% as a colorless solid: ¹H NMR (400 MHz, Acetone-d₆) δ 10.41 (s, 1H), 8.14 (d, J=8.1 Hz, 2H), 7.89 (d, J=8.0 Hz, 2H), 7.70-7.53 (m, 2H), 7.51-7.27 (m, 3H), 5.73 (s, 2H); ¹⁹F NMR (376 MHz, Acetone-d₆) δ −63.58 (s, 3F); HRMS (ESI⁺) m/z calc'd. for C₁₉H₁₃F₃N₅O₃ [M+H]⁺ 416.0965, found 416.0963.

Example 197. Synthesis of 6-((4-(Trifluoromethoxy)phenyl)amino)-[1,2,5]oxadiazolo[3,4-b]pyrazine-5-thiol (1-197)

A round-bottom flask containing 1-2 (0.200 g, 1.05 mmol) and K₂CO₃ (0.200 g, 1.45 mmol) in acetone/H₂O (9:1, 4 mL) was slowly diluted with 4-(trifluoromethoxy)aniline (0.13 mL, 0.97 mmol) and the resulting mixture was stirred at rt. After 1.5 h, the mixture was diluted with a solution of NaSH hydrate in H₂O (0.200 g in 4 mL) and stirring was continued for an additional 30 min. The mixture was acidified with 1M HCl and extracted with EtOAc. The organic layer was washed with brine, dried (MgSO₄), and concentrated to an orange residue. The residue was purified by chromatography on SiO₂ (0.7% MeOH/CH₂Cl₂) to yield 1-197 (53%) as an orange solid: ¹H NMR ((CD₃)₂CO, 500 MHz) δ 13.69 (br s, 1H), 9.91 (s, 1H), 8.17-8.12 (m, 2H), 7.44 (d, J=8.6 Hz, 2H); ¹⁹F NMR ((CD₃)₂CO, 376 MHz) δ−58.78 (s, 3 F); ¹³C NMR ((CD₃)₂CO, 125 MHz) δ 179.0, 152.3, 151.7, 146.6 (q, J_(CF)=2.0 Hz), 143.8, 137.7, 123.9, 122.6, 121.5 (q, J_(CF)=255.4 Hz); HRMS (ES⁺) Yn/z calc'd. for C₁₁H₇F₃N₅O₂S (M+H)⁺330.0267, found 330.0276.

Example 200. Synthesis of 6-ethoxy-N-(2-fluoro-4-(trifluoromethoxy)phenyl)-[1,2,5]oxadiazolo[3,4-B ]pyrazin-5-amine (1-200)

In a 6 dram vial, 1-163 (0.1200 g, 0.348 mmol) was dissolved in 1.70 mL 3:1 ethanol/dioxane. Sodium carbonate (0.1105 g, 1.043 mmol) was added and the mixture was heated to 90° C. and stirred for 16 h. The resulting mixture was concentrated under reduced pressure and purified via flash chromatography (0-15% EtOAc in hexanes) to yield 1-200 in 82% as a yellow solid. ¹H NMR ((CD₃)₂CO, 400 MHz) δ 9.16 (s, 1H), 8.31 (t, 1H, J=8.8 Hz), 7.41-7.36 (m, 1H), 7.35-7.30 (m, 1H), 4.73 (q, 2H, J=7.1 Hz), 1.54 (t, 3H, J=7.1 Hz); ¹³C NMR (100 MHz, Acetone-d₆) δ 155.91 (d, J=250.6 Hz), 155.55, 151.44, 150.74, 148.11, 147.19 (dq, J=10.6, 1.9 Hz), 127.24, 125.29 (d, J=11.3 Hz), 121.27 (q, J=257.0 Hz), 118.04 (d, J=3.8 Hz), 110.42 (dq, J=23.7, 1.2 Hz), 66.84, 14.08; ¹⁹F NMR (376 MHz, Acetone-d₆) δ−58.94 (s, 3F), −120.46-−120.55 (m, 1F); HRMS (ESI): Calc'd. for C₁₃H₁₀F₄N₅O₃ ⁺[M+H]⁺: 360.0720, Observed: 360.0727.

Example 201. Synthesis of N-(2-fluoro-4-(trifluoromethoxy)phenyl)-6-propoxy-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-amine (1-201)

In a 6 dram vial, 1-163 (0.1000 g, 0.290 mmol) was dissolved in 1.33 mL 3:1 propanol/dioxane. Sodium carbonate (0.0921 g, 0.869 mmol) was added and the mixture was heated to 90° C. and stirred for 16 h. The resulting mixture was concentrated under reduced pressure and purified via flash chromatography (0-15% EtOAc in hexanes) to yield 1-201 in 93% as a yellow solid. ¹H NMR ((CD₃)₂CO, 400 MHz) δ 9.14 (s, 1H), 8.32 (t, 1H, J=8.8 Hz), 7.43-7.37 (m, 1H), 7.37-7.30 (m, 1H), 4.65 (t, 2H, J=6.6 Hz), 1.97 (h, 2H, J=7.4 Hz), 1.11 (t, 3H, J=7.4 Hz); ¹³C NMR (100 MHz, Acetone-d₆) δ 155.76, 151.52, 150.81, 148.19, 147.22 (dq, J=10.7, 2.3 Hz), 127.26 (d, J=1.6 Hz), 125.40 (d, J=11.1 Hz), 121.33 (q, J=256.7 Hz), 118.13 (dd, J=3.9, 1.0 Hz), 110.48 (dd, J=23.7, 1.0 Hz), 72.29, 22.28, 10.64; ¹⁹F NMR (376 MHz, Acetone-d₆) δ−58.98 (s, 3F), −120.8-−120.90 (m, 1F); HRMS (ESI): Calc'd. for C₁₄H₁₂F₄N₅O₃ ⁺[M+H]⁺: 374.0871, Observed: 374.0870.

Example 202. Synthesis of N-(2-fluoro-4-(trifluoromethyl)phenyl)-6-methoxy-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-amine (1-202)

Compound 1-202 was synthesized by procedure 1-C using 1-138 to yield 1-202 in 87% as a yellow solid. ¹H NMR ((CD₃)₂CO, 400 MHz) δ 9.23 (s, 1H), 8.63-8.57 (m, 1H), 7.75-7.67 (m, 2H), 4.31 (s, 3H); ¹⁹F NMR (376 MHz, Acetone-d₆) δ −62.86 (s, 3F), −123.84 (t, 1F, J=9.7 Hz).

Example 203. Synthesis of 6-ethoxy-N-(4-(trifluoromethoxy)phenyl)-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-amine (1-203)

In a 6 dram vial, 1-156 (0.1000 g, 0.499 mmol) was dissolved in 1.70 mL 3:1 ethanol/dioxane. Sodium carbonate (0.1600 g, 1.500 mmol) was added and the mixture was heated to 90° C. and stirred for 16 h. The resulting mixture was concentrated under reduced pressure and purified via flash chromatography (0-15% EtOAc in hexanes) to yield 1-203 in 82% as a yellow solid. ¹H NMR (400 MHz, Acetone-d₆) δ 9.65 (s, 1H), 8.16-8.04 (m, 2H), 7.45-7.38 (m, 2H), 4.71 (qd, J=7.0, 1.1 Hz, 2H), 1.51 (qt, J=7.1, 1.0 Hz, 3H). ¹⁹F NMR (376 MHz, Acetone-d₆) δ−58.76 (s 3F). ¹³C NMR (101 MHz, Acetone-d₆) δ 155.80, 151.57, 150.62, 147.77, 146.42 (q, J=2.0 Hz), 137.68, 124.28, 122.37, 121.44 (q, J=255.3 Hz), 66.61, 14.13.

Example 204. Synthesis of 6-(piperidin-1-yl)-[1,2,5]oxadiazolo[3,4-b] pyrazin-5-ol (1-204)

Compound 1-204 was synthesized by procedure 1-C to yield 1-204. ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 12.86 (s, 1H), 4.00 (s, 4H), 1.64 (s, 6H). LC/MS [M−1]⁻=220.1.

Example 205. Synthesis of 6-((4-cyclohexylphenyl)amino)-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-ol (1-205)

Compound 1-205 was synthesized by procedure 1-C 1-205. ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 13.24 (s, 1H), 10.17 (s, 1H), 7.89 (d, J=8.4 Hz, 2H), 7.26 (d, J=8.4 Hz, 2H), 1.8 (d, J=9.6 Hz, 4H), 1.72 (m, 1H), 1.45 (m, 6H). LC/MS [M−1]⁻=310.2.

Example 206. Synthesis of 6-((3-nitrophenyl)amino)-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-ol (1-206)

Compound 1-206 was synthesized by procedure 1-C to yield 1-206. NMR (400 MHz, DMSO-d₆) δ (ppm): 13.36 (s, 1H), 10.70 (s, 1H), 9.10 (m, 1H), 8.46 (dd, J=1.2 Hz, J=1.2 Hz, J=8.4 Hz, 1H), 8.03 (dd, J=1.6 Hz, J=1.6 Hz, J=8.0 Hz, 1H), 7.73 (m, 1H). LC/MS [M−1]⁻=273.0

Example 207. Synthesis of N-(6-methoxy-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-yl)-4-(trifluoromethoxy)benzenesulfonamide (1-207)

Compound 1-207 was synthesized by procedure 1-C to yield 1-207. ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 8.14 (d, J=8.8 Hz, 2H), 7.58 (d, J=8.4 Hz, 2H), 4.03 (s, 3H). LC/MS [M−1]⁻=390.0.

Example 208. Synthesis of 6-((6-(trifluoromethyl)Pyridin-3-yl)amino)-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-ol (1-208)

Compound 1-208 was synthesized by procedure 1-C to yield 1-208. NMR (400 MHz, DMSO-d₆) δ (ppm): 13.41 (s, 1H), 10.81 (s, 1H), 9.29 (d, J=2 Hz, 1H), 8.81 (dd, J=8.4 Hz, 2 Hz, 1H), 8.01 (d, J=8.4 Hz, 1H). LC/MS [M−1]⁻=297.0.

Example 209. Synthesis of 6-(quinolin-5-ylamino)-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-ol (1-209)

Compound 1-209 was synthesized by procedure 1-C to yield 1-209. ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 13.28 (s, 1H), 10.61 (s, 1H), 8.94 (dd, J=4 Hz, 1.2 Hz, 1H), 8.42 (d, J=8.4 Hz, 1H), 8.03 (d, J=8.8 Hz, 1H), 7.84 (t, J=8.4 Hz, 1H), 7.69 (d, J=7.2 Hz, 1H), 7.54 (m, 1H). LC/MS [M−1]⁻=279.0

Example 210. Synthesis of 6-morpholino-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-ol (1-210)

Compound 1-210 was synthesized by procedure 1-C to yield 1-210. ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 12.95 (s, 1H), 4.04 (br s, 4H), 3.72 (t, J=4.8 Hz, 4H). LC/MS [M−1]⁻=222.1.

Example 211. 6-(Azetidin-1-yl)-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-ol (1-211)

Compound 1-211 was synthesized by procedure 1-C using to yield 1-211. ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 12.85 (s, 1H), 4.66 (t, J=7.9 Hz, 2H), 4.16 (t, J=7.9 Hz, 2H), 2.34 (m, 2H). LC/MS [M−1]⁻=192.1.

Example 212. Synthesis of 6-(cyclohexylamino)-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-ol (1-212)

Compound 1-212 was synthesized by procedure 1-C to yield 1-212. ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 13.06 (s, 1H), 8.40 (d, J=8.4 Hz, 1H), 3.87 (m, 1H), 1.82 (m, 4H), 1.62 (m, 1H), 1.40 (m, 4H), 1.07 (m, 1H). LC/MS [M−1]⁻=234.1.

Example 213. 6-((6-(Trifluoromethoxy)Benzo[D]Thiazol-2-yl)amino)-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-ol (1-213)

Compound 1-213 was synthesized by procedure 1-C to yield 1-213. ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 13.40 (s, 1H), 8.25 (d, J=1.6 Hz, 1H), 7.91 (d, J=8.8 Hz, 1H), 7.47 (dd, J=1.6 Hz, J=1.6 Hz, J=8.8 Hz, 1H). LC/MS [M−1]⁻=368.9.

Example 214. Synthesis of 6-(Prop-2-yn-1-ylamino)-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-ol (1-214)

Compound 1-214 was synthesized by procedure 1-C to yield 1-214. ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 13.18 (s, 1H), 9.04 (t, J=6.0 Hz, J=6.0 Hz, 1H), 4.15 (dd, J=2.4 Hz, J=2.4 Hz, J=6.0 Hz, 2H), 3.38 (s, 1H), 3.15 (t, J=2.4 Hz, J=2.4 Hz, 1H)). LC/MS [M−1]⁻=190.1.

Example 215. Synthesis of tert-butyl 4-(6-hydroxy-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-yl)piperazine-1-carboxylate (1-215)

Compound 1-215 was synthesized by procedure 1-C to yield 1-215. ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 12.96 (s, 1H), 3.56 (s, 4H), 3.47 (t, J=5.2 Hz, J=4.4 Hz, 4H), 1.42 (s, 9H). LC/MS [M−1]⁻=321.1.

Example 216. Synthesis of 6-(thiazol-2-ylamino)-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-ol (1-216)

Compound 1-216 was synthesized by procedure 1-C to yield 1-216. ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 13.31 (s, 1H), 7.64 (d, J=3.2 Hz, 1H), 7.45 (d, J=3.6 Hz, 1H). LC/MS [M+1]⁺=237.1.

Example 217. Synthesis of 5,6-dichloro-3-nitropyridin-2-amine (1-217)

To a suspension of 6-chloro-3-nitropyridin-2-amine (20 g, 115 mmol) in acetic acid (100 mL) was added NCS (16.2 g, 121 mmol), and the obtained reaction mixture was stirred at 100° C. for one hour. The reaction mixture was allowed to cool to room temperature, and additional NCS (2.00 g) was added thereto. The obtained reaction mixture was stirred at 100° C. for 1 h. The obtained reaction mixture was allowed to cool to r.t. and acetic acid was removed via distillation. The residue was suspended in water and quenched with sat. aq. sodium bicarbonate until pH=8 and the solid residue was filtered and washed twice with water. The solid was collected, dissolved in acetone and precipitated with water, and filtered to afford 1-217 as a pure yellow solid (11 g, 46%). ¹H NMR (400 MHz, DMSO-d₆) δ 8.59 (s, 1H), 8.34 (s, 2H).

Example 218. 5,6-dichloro-[1,2,5]oxadiazolo[3,4-b]pyridine 1-oxide (1-218)

Pyridine 1-217 (4.50 g, 21.6 mmol) and iodobenzene diacetate (17.421 g, 54.087 mmol) were added to a sealed tube and stirred in acetone (100 mL) at 80° C. for 16 h. The reaction was then concentrated under reduced pressure to remove the solvent. Residual acetic acid was removed via distillation at 110° C. under reduced pressure. The resulting crude product was purified by silica gel chromatography (0-100% ethyl acetate/hexanes) to afford 1-218 as a yellow solid (2.00 g, 45%). 1H NMR (400 MHz, Acetone-d₆) δ 8.52 (s, 1H).

Example 219. Synthesis of 5,6-dichloro-[1,2,5]oxadiazolo[3,4-b]pyridine (1-219)

In a dry flask, 1-218 (1.000 g, 14.56 mmol) was dissolved in dry DCM (50 mL) and triphenylphosphine (3.82 g, 14.6 mmol) was added slowly at 0° C. under argon. The mixture was stirred at 35° C. for 24 hours. The reaction was concentrated under reduced pressure, diluted with saturated sodium bicarbonate, and extracted with ethyl acetate 3×. All organic fractions were combined, dried over anhydrous sodium sulfate, concentrated and purified via silica gel chromatography (Ethyl Acetate Hexanes 0-5%) to afford 1-219 as an off white solid (1.00 g, 54%). ¹H NMR (500 MHz, Acetone-d₆) δ 8.90 (s, 1H). ¹³C NMR (126 MHz, Acetone-d₆) δ 158.79, 157.25, 144.06, 134.70, 127.03.

Example 220. 6-chloro-5-methoxy-[1,2,5]oxadiazolo[3,4-b]pyridine (1-220)

In a flame dried flask, NaH (0.13 g, 3.2 mmol 60% w/w dispersion) was added to dry THF (10 mL) and allowed to stir under argon for 1 min Methanol (141 μL, 3.47 mmol) in dry THF (5 mL) was added dropwise over a minute, and the mixture was allowed to stir for 10 min. 1-219 (600 mg 3.16 mmol) in dry THF (5 mL) was then added dropwise over 1 min. and the mixture was allowed to stir at r.t. for 30 min. The mixture was then reduced under pressure, and purified via silica gel chromatography (Ethyl acetate: Hexanes 0-5%) to afford 1-220 as a white crystalline solid (538 mg, 92%). ¹H NMR (500 MHz, Acetone-d₆) δ 8.57 (s, 1H), 4.21 (s, 3H).

Example 221. Synthesis of N-(2-fluorophenyl)-5-methoxy-[1,2,5]oxadiazolo[3,4-b]pyridin-6-amine (1-221)

Using procedure 1-J, 1-221 was afforded as a yellow solid (55 mg, 52%). ¹H NMR (500 MHz, Acetone-d₆) δ 7.92 (s, 1H), 7.62-7.57 (m, 1H), 7.37-7.29 (m, 3H), 6.82 (d, J=2.2 Hz, 1H), 4.24 (s, 3H). ¹³C NMR (126 MHz, Acetone-d₆) δ161.17, 157.36 (d, J=247.4 Hz), 154.89, 144.20, 136.93, 128.23 (d, J=8.1 Hz), 127.34 (d, J=12.9 Hz), 127.32 (d, J=2.0 Hz), 126.09 (d, J=3.9 Hz), 117.46 (d, J=19.9 Hz), 93.71 (d, J=2.7 Hz), 56.19. HRMS (ESI⁺) m/z calc'd. for C₁₂H₁₀FN₄O₂ (M+H)⁺261.0782, found 261.0781.

Example 222. Synthesis of 6-((2-fluorophenyl)amino)-[1,2,5]oxadiazolo[3,4-b]pyridin-5-ol (1-222)

Using procedure 1-K, 1-222 was afforded as a yellow solid (10 mg, 70%). ¹H NMR −(500 MHz, Acetone-d₆) δ 11.81 (s, 1H), 7.93 (s, 1H), 7.70-7.61 (m, 1H), 7.36-7.28 (m, 3H), 6.82-6.76 (m, 1H). ¹³C NMR (126 MHz, Acetone-d₆) δ158.72, 155.68 (d, J=246.6 Hz), 147.72, 142.00, 138.17, 126.69 (d, J=11.7 Hz), 126.53 (d, J=8.3 Hz), 125.13 (d, J=4.5 Hz), 124.72 (d, J=3.7 Hz), 116.62-116.04 (m), 89.83 (d, J=2.8 Hz). HRMS (ESI⁺) m/z calc'd. for C₁₁H₈FN₄O₂+(M+H)⁺247.0626, found 247.0622.

Example 223. Synthesis of 5-methoxy-N-(4-(trifluoromethoxy)phenyl)-[1,2,5]oxadiazolo[3,4-b]pyridin-6-amine (1-223)

Using procedure 1-J, 1-223 was afforded as a white solid (158 mg, 72%). ¹H NMR (500 MHz, Acetone-d₆) δ 8.34 (s, 1H), 7.62-7.52 (m, 2H), 7.43 (dq, J=2.3, 1.2 Hz, 1H), 7.41-7.36 (m, 1H), 7.17-7.10 (m, 1H), 4.21 (s, 3H). HRMS (ESI⁺) m/z calc'd. for C₁₃H₁₀F₃N₄O₃+(M+H)⁺327.0700, found 327.0701.

Example 224. Synthesis of 6-((4-(trifluoromethoxy)phenyl)amino)-[1,2,5]oxadiazolo[3,4-b]pyridin-5-ol (1-224)

Using procedure 1-K was afforded 1-224 as a yellow solid. ¹H NMR (500 MHz, Acetone-d₆) δ 11.77 (s, 1H), 8.22 (s, 1H), 7.70-7.51 (m, 2H), 7.48-7.37 (m, 2H), 7.11 (s, 1H). ¹³C NMR (126 MHz, Acetone-d₆) δ 159.67, 148.57, 145.93 (q, J=2.2 Hz), 142.95, 139.29, 138.92, 124.37, 123.21, 121.48 (q J=255.2 Hz), 90.38. HRMS (ESI⁺) m/z calc'd. for C₁₂H₈F₃N₄O₃+(M+H)⁺313.0543, found 313.0543.

Example 225. 5-methoxy-N-(4-(6-(trifluoromethyl)pyridin-3-yl)phenyl)-[1,2,5]oxadiazolo[3,4-b]pyridin-6-amine (1-225)

Using procedure 1-J, 1-225 was afforded as a yellow solid (93 mg, 36%). ¹H NMR (500 MHz, Acetone-d6) δ 9.08 (d, J=2.4 Hz, 1H), 8.54-8.29 (m, 2H), 7.96-7.88 (m, 3H), 7.72-7.58 (m, 2H), 7.41 (s, 1H), 4.22 (s, 3H). ¹³C NMR (126 MHz, Acetone-d6) δ 161.44, 154.86, 148.96, 146.79 (q, J=34.5 Hz), 144.21, 141.30, 139.63-139.54 (m), 136.22, 136.02, 132.73, 129.44, 123.42, 122.95 (q, J=272.8 Hz), 121.51 (q, J=3.1 Hz), 94.14, 56.16. HRMS (ESI⁺) m/z calc'd. for C₁₈H₁₃F₃N₅O₂+(M+H)⁺388.1016, found 388.1017.

Example 226. 5-methoxy-N-(4-(trifluoromethoxy)phenyl)-[1,2,5]oxadiazolo [3,4-b]pyridin-6-amine (1-226)

Using procedure 1-J, 1-226 was afforded as a yellow solid (182 mg 83%). ¹H NMR (500 MHz, Acetone-d₆) δ 8.26 (s, 1H), 7.64-7.57 (m, 2H), 7.45-7.40 (m, 2H), 7.28 (s, 1H), 4.21 (s, 3H). ¹³C NMR (126 MHz, Acetone-d₆) δ161.38, 154.85, 146.12 (d, J=2.4 Hz), 144.20, 139.40, 136.49, 124.90, 123.28, 120.44 (q, J=254.7 Hz), 93.61, 56.14. HRMS (ESI⁺) m/z calc'd. for C₁₃H₁₀F₃N₄O₃+(M+H)⁺327.0700, found 327.0701.

Example 227. Synthesis of 5-methoxy-N-(4-(6-(trifluoromethyl)pyridin-3-yl)phenyl)-[1,2,5]oxadiazolo[3,4-b]pyridin-6-amine (1-227)

Using procedure 1-J, 1-227 was afforded as a white solid (60 mg 54%). ¹H NMR (500 MHz, Acetone-d6) δ 8.35 (s, 1H), 7.59-7.46 (m, 3H), 7.42 (ddd, J=8.9, 2.7, 1.4 Hz, 1H), 4.19 (s, 3H). ¹³C NMR (126 MHz, Acetone-d6) δ 161.30, 155.65 (d, J=250.4 Hz), 154.89, 144.05, 141.24 (d, J=9.6 Hz), 135.53, 132.82-132.23 (m), 125.77, 121.50 (d, J=256.5 Hz), 118.95 (d, J=3.8 Hz), 111.35 (d, J=21.9 Hz), 95.64, 56.18. HRMS (ESI⁺) m/z calc'd. for C₁₃H9F₄N₄O₃+(M+H)⁺345.0605, found 345.0604.

Example 228. Synthesis of 5-methoxy-N-(4-(trifluoromethyl)Phenyl)-[1,2,5]oxadiazolo[3,4-b]pyridin-6-amine (1-228)

Using procedure 1-J, 1-228 was afforded as a yellow solid (49 mg 59%). ¹H NMR (500 MHz, Acetone-d6) δ 8.47-8.37 (m, 1H), 7.78-7.73 (m, 2H), 7.71-7.65 (m, 2H), 7.53 (dd, J=6.0, 2.9 Hz, 1H), 4.21-4.18 (m, 3H). ¹³C NMR (126 MHz, Acetone-d6) δ161.39 (d, J=2.3 Hz), 154.90 (d, J=2.6 Hz), 144.19, 144.04, 135.26, 127.55 (q, J=4.4 Hz), 126.09 (q, J=270.2 Hz), 125.60 (q, J=32.6 Hz), 122.08, 95.74, 56.17. HRMS (ESI⁺) m/z calc'd. for C₁₃H₁₀F₃N₄O₂+(M+H)⁺311.0750, found 311.0749.

Example 229. Synthesis of 6-((3-(trifluoromethoxy)phenyl)amino)-[1,2,5]oxadiazolo[3,4-b]pyridin-5-ol (1-229)

Using procedure 1-K, 1-229 was afforded as an off white solid (8 mg, 60%). ¹H NMR (500 MHz, Acetone-d6) δ 11.77 (s, 1H), 8.31 (s, 1H), 7.65-7.54 (m, 2H), 7.49 (dt, J=2.0, 0.9 Hz, 1H), 7.21 (s, 1H), 7.17-7.09 (m, 1H). ¹³C NMR (126 MHz, Acetone-d6) δ 159.64, 150.65 (d, J=2.2 Hz), 148.64, 142.90, 142.03, 138.50, 131.90, 121.43 (q, J=255.9 Hz), 121.04, 117.08, 115.25, 91.36. HRMS (ESI⁻) m/z calc'd. for C₁₂H₆F₃N₄O₃−(M−H)⁻311.0397, found 311.0407.

Example 230. Synthesis of 6-((3-fluoro-4-(trifluoromethoxy)phenyl)amino)-[1,2,5]oxadiazolo[3,4-b]pyridin-5-ol (1-230)

Using procedure 1-K, 1-230 was afforded as an off-white solid (7 mg, 50%). ¹H NMR (400 MHz, Acetone-d6) δ 8.33 (s, 1H), 7.63-7.51 (m, 2H), 7.51-7.44 (m, 1H), 7.31 (d, J=0.5 Hz, 1H). ¹⁹F NMR (376 MHz, Acetone-d6) δ−59.94 (d, J=5.0 Hz, 3F), −126.83-−130.27 (m, 1F). ¹³C NMR (126 MHz, Acetone-d6) δ 159.59, 155.62 (d, J=250.2 Hz), 148.68, 142.84, 141.08 (d, J=9.7 Hz), 138.19, 132.42 (dt, J=15.4, 2.4 Hz), 125.74, 121.51 (q, J=256.4 Hz), 118.66 (d, J=3.8 Hz), 111.11 (d, J=22.0 Hz), 92.28. HRMS (ESI⁻) m/z calc'd. for C₁₂H₅F₄N₄O₃−(M−H)⁻329.0303, found 329.0302.

Example 231. Synthesis of 6-((4-(6-(trifluoromethyl)pyridin-3-yl)phenyl)amino)-[1,2,5]oxadiazolo[3,4-b]pyridin-5-ol (1-231)

Using procedure 1-K, 1-231 was afforded as a yellow solid (8 mg, 60%). ¹H NMR (500 MHz, Acetone-d6) δ 11.80 (s, 1H), 9.09 (d, J=2.1 Hz, 1H), 8.37 (dd, J=8.2, 2.2 Hz, 1H), 8.30 (s, 1H), 8.08-7.81 (m, 3H), 7.71 (d, J=8.5 Hz, 2H), 7.25 (s, 1H). ¹³C NMR (126 MHz, Acetone-d6) δ 159.76, 148.98, 148.60, 146.79 (d, J=34.1 Hz), 143.00, 141.17, 139.60, 138.49, 136.24, 132.57, 129.41, 123.01, 122.97 (q, J=273.3 Hz), 121.52 (q, J=3.2 Hz), 90.93. HRMS (ESI⁻) m/z calc'd. for C₁₇H₉F₃N₅O₂−(M−H)⁻372.0714, found 372.0713.

Example 232. 6-((2-fluoro-3-(trifluoromethyl)phenyl)amino)-[1,2,5]oxadiazolo[3,4-b]pyridin-5-ol (1-232)

Using procedure 1-K, 1-232 was afforded as a white solid (7 mg, 50%). ¹H NMR (400 MHz, Acetone-d6) δ 8.10 (s, 1H), 8.05-7.96 (m, 1H), 7.68-7.58 (m, 1H), 7.57-7.49 (m, 1H), 6.94 (d, J=1.6 Hz, 1H) OH not visible. ¹⁹F NMR (376 MHz, Acetone-d6) δ−61.80 (d, J=13.0 Hz, 3F), −127.06 (qt, J=13.0, 6.9 Hz 1F). ¹³C NMR (126 MHz, Acetone-d6) δ 159.49, 153.49 (d, J=256.3 Hz), 148.74, 142.76, 138.78, 129.97, 129.34 (d, J=10.8 Hz), 126.26 (d, J=5.0 Hz), 123.98-123.65 (m), 123.64 (d, J=271.8 Hz), 119.89-119.37 (m), 91.99 (d, J=2.6 Hz). HRMS (ESI⁻) m/z calc'd. for C₁₂H₅F₄N₄O₂−(M−H)⁻313.0354, found 313.0364.

Example 233. Synthesis of 5-methoxy-N-(3-(trifluoromethyl)phenyl)-[1,2,5]oxadiazolo[3,4-B]pyridin-6-amine (1-233)

Using procedure 1-J, 1-233 was afforded as a white solid (78 mg, 78%). ¹H NMR (500 MHz, Acetone-d6) δ 8.35 (s, 1H), 7.83-7.79 (m, 1H), 7.76 (s, 1H), 7.68 (t, J=7.9 Hz, 1H), 7.51 (d, 1H), 7.36 (s, 1H), 4.21 (s, 3H). ¹³C NMR (126 MHz, Acetone-d6) δ 161.35, 154.88, 144.10, 141.27, 136.03, 132.19 (q, J=32.2 Hz), 131.46, 126.37 (d, J=1.7 Hz), 125.01 (q, J=271.2 Hz), 121.56 (q, J=4.1 Hz), 119.70 (q, J=4.3 Hz), 94.46, 56.16. HRMS (ESI⁺) m/z calc'd. for C₁₃H₁₀F₃N₄O₂+(M+H)⁺311.0750, found 311.0749.

Example 234. Synthesis of 6-((3-(trifluoromethyl)phenyl)amino)-[1,2,5]oxadiazolo[3,4-b]pyridin-5-ol (1-234)

Using procedure 1-K, 1-234 was afforded as a yellow solid (5 mg, 30%). ¹H NMR (400 MHz, Acetone-d6) δ 11.77 (s, 1H), 8.35 (s, 1H), 7.88-7.78 (m, 2H), 7.70 (tt, J=7.9, 0.9 Hz, 1H), 7.51 (ddt, J=7.8, 1.8, 0.9 Hz, 1H), 7.20 (s, 1H). ¹⁹F NMR (376 MHz, Acetone-d6) δ−63.31 (s, 3F). HRMS (ESI⁻) m/z calc'd. for C₁₂H₆F₃N₄O₂−(M−H)⁻295.0448, found 295.0446.

Example 235. Synthesis of N-(2-fluoro-4-(trifluoromethoxy)phenyl)-5-methoxy-[1,2,5]oxadiazolo[3,4-b]pyridin-6-amine (1-235)

Using procedure 1-J, 1-235 was afforded as a yellow solid (146 mg, 79%). ¹H NMR (500 MHz, Acetone-d6) δ 8.00 (s, 1H), 7.74 (t, J=8.8 Hz, 1H), 7.46-7.38 (m, 1H), 7.36-7.30 (m, 1H), 6.92 (d, J=2.2 Hz, 1H), 4.24 (s, 3H). 13C NMR (126 MHz, Acetone-d6) δ160.22, 156.35 (d, J=251.1 Hz), 154.06, 143.24, 135.78, 127.48 (d, J=3.1 Hz), 126.01 (d, J=12.3 Hz), 120.43 (q, J=256.4 Hz), 117.93 (d, J=4.6 Hz), 110.70, 110.50, 93.72 (d, J=2.8 Hz), 55.33. HRMS (ESI⁺) m/z calc'd. for C₁₃H₉F₄N₄O₃+(M+H)⁺345.0605, found 345.0605.

Example 236. Synthesis of 5-methoxy-N-(p-tolyl)-[1,2,5]oxadiazolo[3,4-b]pyridin-6-amine (1-236)

Using procedure 1-J, 1-236 was afforded as a yellow solid (78 mg, 56%). ¹H NMR (400 MHz, Acetone-d6) δ 8.04 (s, 1H), 7.38-7.22 (m, 4H), 7.06 (s, 1H), 4.20 (s, 3H), 2.35 (d, J=0.7 Hz, 3H). 13C NMR (126 MHz, Acetone-d₆) δ161.41, 154.75, 144.34, 137.32 (d, J=5.6 Hz), 135.47, 130.95, 124.02, 123.91, 91.86, 56.04, 20.93. HRMS (ESI⁺) m/z calc'd. for C₁₃H₁₃N₄O₂+(M+H)⁺257.1033, found 257.1033.

Example 237. Synthesis of N-(2,3-difluorophenyl)-5-methoxy-[1,2,5]oxadiazolo[3,4-b]pyridin-6-amine (1-237)

Using procedure 1-J, 1-237 was afforded as a yellow solid (118 mg, 79%). ¹H NMR (500 MHz, Acetone-d6) δ 8.05 (s, 1H), 7.46-7.39 (m, 1H), 7.36-7.22 (m, 2H), 6.98 (d, J=2.3 Hz, 1H), 4.24 (s, 3H). 13C NMR (126 MHz, Acetone-d6) δ161.11, 154.95, 152.18 (dd, J=246.6, 11.5 Hz), 145.77 (dd, J=249.1, 14.0 Hz), 144.11, 136.50, 129.75-129.35 (m), 125.72 (dd, J=8.7, 5.1 Hz), 122.17 (d, J=3.6 Hz), 115.01 (d, J=17.4 Hz), 94.93 (d, J=2.8 Hz), 56.22. HRMS (ESI⁺) m/z calc'd. for C₁₂H₉F₂N₄O₂+(M+H)⁺279.0688, found 279.0689.

Example 238. Synthesis of 5-methoxy-N-(2-methyl-4-(trifluoromethoxy)phenyl)-[1,2,5]oxadiazolo[3,4-b]pyridin-6-amine (1-238)

Using procedure 1-J, 1-238 was afforded as a yellow solid (37 mg, 20%). ¹H NMR (500 MHz) δ 7.84 (s, 1H), 7.52 (d, J=9.0 Hz, 1H), 7.37 (d, J=3.9 Hz, 1H), 7.32-7.24 (m, 1H), 6.46 (s, 1H), 4.23 (s, 3H), 2.34 (s, 3H). HRMS (ESI⁺) m/z calc'd. for C₁₄H₁₂F₃N₄O₃+(M+H)⁺341.0856, found 341.0857.

Example 239. Synthesis of 6-((3-(tert-butyl)phenyl)amino)-[1,2,5]oxadiazolo[3,4-b]pyridin-5-ol (1-239)

Using procedure 1-K, 1-239 was afforded as a beige solid (12 mg, 84%). ¹H NMR (400 MHz, Acetone-d6) δ 11.75 (s, 1H), 8.07 (s, 1H), 7.50 (t, J=2.0 Hz, 1H), 7.40 (t, J=7.8 Hz, 1H), 7.35-7.30 (m, 1H), 7.29-7.24 (m, 1H), 6.99 (s, 1H), 1.35 (s, 9H). ¹³C NMR (126 MHz, Acetone-d6) δ 158.93, 152.71, 147.59, 142.20, 138.79, 138.43, 129.13, 121.61, 119.70, 119.03, 88.17, 30.64, 29.70. HRMS (ESI+) m/z calc'd. for C₁₅H₁₇N₄O₂+(M+H)⁺285.1346, found 285.1343.

Example 240. Synthesis of 6-((3-fluorophenyl)amino)-[1,2,5]oxadiazolo[3,4-b]pyridin-5-ol (1-240)

Using procedure 1-K, 1-240 was afforded as a yellow solid (12 mg, 85%). ¹H NMR (400 MHz, Acetone-d6) δ 11.80 (s, 1H), 8.21 (s, 1H), 7.53-7.45 (m, 1H), 7.39-7.29 (m, 2H), 7.23-7.20 (m, 1H), 6.98-6.91 (m, 1H). ¹⁹F NMR (376 MHz, Acetone-d6) δ−112.96-−113.08 (m, 1F). ¹³C NMR (126 MHz, Acetone-d6) δ 164.20 (d, J=243.9 Hz), 159.66, 148.57, 142.92, 142.04 (d, J=10.7 Hz), 138.48, 131.89 (d, J=9.9 Hz), 118.25 (d, J=3.3 Hz), 111.57 (d, J=21.6 Hz), 109.46 (d, J=24.8 Hz), 91.17. HRMS (ESI⁺) m/z calc'd. for C₁₁H₈FN₄O₂+(M+H)+247.0626, found 247.0624.

Example 241. Synthesis of 6-((4-methoxyphenyl)amino)-[1,2,5]oxadiazolo[3,4-b]pyridin-5-ol (1-241)

Using procedure 1-K, 1-241 was afforded as a yellow solid (10 mg, 70%). ¹H NMR (400 MHz, Acetone-d6) δ 11.70 (s, 1H), 7.93 (s, 1H), 7.41-7.35 (m, 2H), 7.06-7.00 (m, 2H), 6.73 (s, 1H), 3.83 (s, 3H). HRMS (ESI) m/z calc'd. for C₁₂H₁₀N₄O₃ (M·)+258.0753, found 258.0751.

Example 242. Synthesis of 6-((4-(trifluoromethyl)phenyl)amino)-[1,2,5]oxadiazolo[3,4-b]pyridin-5-ol (1-242)

Using procedure 1-K, 1-242 was afforded as a yellow solid (12 mg, 75%). ¹H NMR (400 MHz, Acetone-do) δ 11.84 (s, 1H), 8.39 (s, 1H), 7.82-7.71 (m, 4H), 7.36 (d, J=3.7 Hz, 1H). HRMS (ESI⁻) m/z calc'd. for C₁₂H₆F₃N₄O₂−(M−H)⁻ 295.0448, found 295.0456.

Example 243. Synthesis of 6-((3,5-bis(trifluoromethyl)phenyl)amino)-[1,2,5]oxadiazolo[3,4-b]pyridin-5-ol (1-243)

Using procedure 1-K, 243 was afforded as a beige solid (8 mg, 60%). HRMS (ESI) m/z calc'd. for C₁₃H₅F₆N₄O₂−(M−H)−363.0322, found 363.0332.

Example 244. Synthesis of 5-methoxy-N-(4-methoxyphenyl)-[1,2,5]oxadiazolo[3,4-b]pyridin-6-amine (1-244)

Using procedure 1-J, 1-244 was afforded as a yellow solid (99 mg, 67%). ¹H NMR (500 MHz, Acetone-d₆) δ 7.96 (s, 1H), 7.36 (dd, J=8.8, 1.7 Hz, 2H), 7.10-6.97 (m, 2H), 6.87 (d, J=6.3 Hz, 1H), 4.20 (s, 3H), 3.84 (s, 3H). ¹³C NMR (126 MHz, Acetone-do) δ161.35, 158.37, 154.73, 144.39, 138.05, 132.33, 126.42, 126.34, 115.66, 91.04, 56.01, 55.77. HRMS (ESI⁺) m/z calc'd. for C₁₃H₁₃N₄O₃+(M+H)⁺273.0982, found 273.0982.

Example 245. 6-(p-tolylamino)-[1,2,5]oxadiazolo[3,4-b]pyridin-5-ol (1-244)

Using procedure 1-K, 1-244 was afforded as a yellow solid (12 mg, 85%). ¹H NMR (400 MHz, Acetone-d₆) δ 11.73 (s, 1H), 7.99 (s, 1H), 7.39-7.31 (m, 2H), 7.30-7.25 (m, 2H), 6.92 (s, 1H), 2.34 (d, J=0.7 Hz, 3H). HRMS (ESI⁺) m/z calc'd. for C₁₂H₁₁N₄O₂+(M+H)⁺243.0877, found 243.0875.

Example 246. N-(3-(tert-butyl)phenyl)-5-methoxy-[1,2,5]oxadiazolo[3,4-b]pyridin-6-amine (1-246)

Using procedure 1-J, 1-246 was afforded as a tan solid (94 mg, 58%). ¹H NMR (500 MHz, Acetone-d₆) δ 8.11 (s, 1H), 7.49 (t, J=2.0 Hz, 1H), 7.42 (t, J=7.9 Hz, 1H), 7.31 (dddd, J=9.8, 7.8, 2.1, 1.1 Hz, 2H), 7.15 (s, 1H), 4.23 (s, 3H), 1.36 (s, 9H). ¹³C NMR (126 MHz, Acetone-d₆) δ161.45, 154.76, 153.65, 144.33, 139.74, 137.04, 130.07, 122.75, 121.08, 120.62, 92.22, 56.08, 35.37, 31.52. HRMS (ESI⁺) m/z calc'd. for C₁₆H₁₉N₄O₂+(M+H)⁺299.1503, found 299.1502.

Example 247. Synthesis of N-(3-fluorophenyl)-5-methoxy-[1,2,5]oxadiazolo[3,4-b]pyridin-6-amine (1-247)

Using procedure 1-J, 1-247 was afforded as a yellow solid (94 mg, 67%). ¹H NMR (500 MHz, Acetone-d6) δ 8.26 (s, 1H), 7.53-7.44 (m, 1H), 7.40-7.35 (m, 1H), 7.35-7.29 (m, 1H), 7.29-7.23 (m, 1H), 6.98-6.91 (m, 1H), 4.20 (s, 3H). ¹³C NMR (126 MHz, Acetone-d6) δ164.24 (d, J=243.4 Hz), 161.39, 154.86, 144.18, 142.18, 136.04, 131.95 (d, J=9.9 Hz), 118.72 (d, J=3.0 Hz), 112.04-111.21 (m), 110.33-109.58 (m), 94.45, 56.14. HRMS (ESI⁺) m/z calc'd. for C₁₂H₁₀FN₄O₂+(M+H)⁺261.0782, found 261.0782.

Example 248. Synthesis of N-(3,5-bis(trifluoromethyl)phenyl)-5-methoxy-[1,2,5]oxadiazolo[3,4-b]pyridin-6-amine (1-248)

Using procedure 1-J, 1-248 was afforded as a beige solid (139 mg, 68%). ¹H NMR (500 MHz, Acetone-d6) δ 8.58 (s, 1H), 8.11 (d, J=1.6 Hz, 2H), 7.77 (s, 1H), 7.65 (s, 1H), 4.23 (s, 3H). ¹³C NMR (126 MHz, Acetone-d6) δ 161.46, 155.12, 144.02, 143.02, 135.33, 133.31 (d, J=33.4 Hz), 124.28 (q, J=272.2 Hz), 122.45 (d, J=4.5 Hz), 117.60 (q, J=4.2 Hz), 97.23, 56.26. HRMS (ESI⁺) m/z calc'd. for C₁₄H₉F₆N₄O₂+(M+H)⁺379.0624, found 379.0621.

Example 249. Synthesis of N-(2-fluoro-3-(trifluoromethyl)phenyl)-5-methoxy-[1,2,5]oxadiazolo[3,4-b]pyridin-6-amine (1-249)

Using procedure 1-J, 1-249 was afforded as a yellow solid (78 mg, 73%). ¹H NMR (500 MHz, Acetone-d6) δ 8.06 (s, 1H), 8.01-7.90 (m, 1H), 7.70-7.60 (m, 1H), 7.52 (t, J=7.9, 1H), 7.02 (d, J=2.0 Hz, 1H), 4.24 (s, 3H). ¹³C NMR (126 MHz, Acetone-d6) δ 161.11, 154.97, 154.24 (dq, J=256.8, 2.2 Hz), 144.04, 136.34, 131.28 (d, J=2.3 Hz), 129.21 (d, J=11.3 Hz), 126.29 (d, J=5.1 Hz), 124.47 (q, J=5.4 Hz), 123.63 (q, J=272.0 Hz), 120.30-119.35 (m), 95.16 (d, J=2.7 Hz), 56.26. HRMS (ESI⁺) m/z calc'd. for C₁₃H₉F₄N₄O₂+(M+H)⁺329.0656, found 329.0657.

Example 250. 6-((2,3-difluorophenyl)amino)-[1,2,5]oxadiazolo[3,4-b]pyridin-5-ol (1-250)

Using procedure 1-K, 1-250 was afforded as a yellow solid (12 mg, 84%). ¹H NMR (400 MHz, Acetone-d6) δ 11.87 (s, 1H), 8.04 (s, 1H), 7.52-7.45 (m, 1H), 7.36-7.27 (m, 1H), 7.27-7.17 (m, 1H), 6.94-6.88 (m, 1H). ¹⁹F NMR (376 MHz, Acetone-d₆) δ−138.36-−139.25 (m, 1F), −148.82-149.48 (m, 1F). HRMS (ESI−) m/z calc'd. for C₁₁H₅F₂N₄O₂−(M−H)−263.0386, found 263.0391.

Example 251. Synthesis of 6-((2-fluoro-4-(trifluoromethoxy)phenyl)amino)-[1,2,5]oxadiazolo[3,4-b]pyridin-5-ol (1-251)

Using procedure 1-K, 1-251 was afforded as a beige solid (16 mg, 93%). ¹H NMR (400 MHz, Acetone-d6) δ 11.86 (s, 1H), 8.00 (s, 1H), 7.83-7.76 (m, 1H), 7.45-7.40 (m, 1H), 7.36-7.30 (m, 1H), 6.85 (d, J=1.8 Hz, 1H). ¹⁹F NMR (376 MHz, Acetone-d6) δ−59.04, −119.24-−119.74 (m). ¹³C NMR (126 MHz, Acetone-d6) δ 159.85-159.05 (m), 156.48 (dd, J=250.4, 10.9 Hz), 148.62 (d, J=14.7 Hz), 147.13-146.16 (m), 142.79, 138.88 (d, J=18.7 Hz), 127.21-126.94 (m), 126.80 (d, J=3.1 Hz), 126.62 (d, J=3.2 Hz), 122.35 (q, J=256.4 Hz), 118.75, 111.31 (d, J=24.3 Hz), 91.77-91.24 (m). HRMS (ESI−) m/z calc'd. for C₁₂H₅F₄N₄O₃−(M−H)−329.0303, found 329.0311.

Additional Compounds of the Disclosure

Example 252. Biological Activity of Compounds

Biological activities of the compounds synthesized is determined by determining increase in oxygen consumption rate (OCR).

Oxygen consumption rate (OCR) in whole cells is measured in general accordance with the method of Kenwood B M et al. (Mol. Met. (2014) 3: 114-123).

OCR is measured using a Seahorse XF-24 Flux Analyzer (Seahorse Biosciences, North Billerica, Mass.). NMuLi, C2C12, and L6 cells are seeded in a Seahorse 24-well tissue culture plate at a density of 3.5×10⁴ cells/well, isolated cardiomyocytes at a density of 4×10⁴ cells/well, and human primary fibroblasts at a density of 1.1×10⁴ cells/well. The cells are then allowed to adhere for 24 h. Prior to the assay, the media is changed to unbuffered DMEM containing pyruvate and glutamine (Gibco #12800-017, pH=7.4 at 37° C.) and the cells are equilibrated for 30 mins at 37° C. Compounds are injected during the assay and OCR is measured using 2 min measurement periods.

2-3 wells are used per condition and averaged over three plates (n=6-9). Statistical significance is determined by two-way ANOVA with Bonferroni's posttest.

The activity (increase in OCR) are presented in TABLE 1. Activities are reported as binned EC₅₀ values: A=5 μM or less; B=>5 to 20 μM; C=over 20 μM; NA=not active.

Compound OCR Number Activity 1-3 B 1-4 C 1-5 C 1-6 B 1-7 B 1-8 A 1-9 A 1-10 B 1-11 A 1-12 B 1-13 NA 1-14 B 1-15 B 1-16 A 1-17 B 1-18 B 1-19 B 1-20 B 1-21 B 1-22 A 1-23 NA 1-24 A 1-25 A 1-26 C 1-27 C 1-28 B 1-29 A 1-30 A 1-31 A 1-32 A 1-33 B 1-34 B 1-35 A 1-36 A 1-37 A 1-38 A 1-39 A 1-40 C 1-41 A 1-42 B 1-43 A 1-44 A 1-45 NA 1-46 B 1-47 C 1-48 NA 1-49 NA 1-50 B 1-51 A 1-52 C 1-53 A 1-54 A 1-55 A 1-56 A 1-57 NA 1-58 C 1-59 NA 1-60 B 1-61 B 1-62 A 1-63 A 1-64 A 1-65 B 1-66 A 1-67 A 1-68 B 1-69 A 1-70 B 1-71 C 1-72 B 1-73 NA 1-74 A 1-75 NA 1-76 NA 1-77 C 1-78 C 1-79 C 1-80 C 1-81 B 1-82 A 1-83 B 1-84 NA 1-85 C 1-86 A 1-87 C 1-88 C 1-89 B 1-90 B 1-91 B 1-92 A 1-93 B 1-94 C 1-95 A 1-96 A 1-97 A 1-98 B 1-99 A 1-100 A 1-101 NA 1-103 A 1-104 A 1-105 B 1-106 B 1-107 B 1-108 A 1-109 A 1-110 B 1-111 B 1-112 A 1-113 A 1-114 A 1-115 C 1-116 B 1-117 B 1-118 A 1-119 A 1-120 A 1-121 A 1-122 C 1-123 A 1-124 A 1-125 A 1-126 A 1-127 C 1-128 C 1-129 B 1-130 B 1-131 A 1-132 A 1-133 A 1-134 A 1-135 A 1-136 A 1-137 A 1-139 NA 1-140 NA 1-141 NA 1-142 NA 1-143 NA 1-144 NA 1-145 NA 1-146 NA 1-147 NA 1-148 NA 1-149 NA 1-150 NA 1-151 NA 1-156 NA 1-176 NA 1-180 NA 1-186 NA 1-187 NA 1-188 NA 1-189 NA 1-190 A 1-191 NA 1-192 NA 1-193 NA 1-194 NA 1-195 NA 1-196 B 1-197 NA 1-200 NA 1-201 NA 1-202 NA 1-204 NA 1-205 A 1-206 C 1-207 NA 1-208 C 1-209 NA 1-210 NA 1-211 NA 1-212 C 1-213 NA 1-214 NA 1-215 NA 1-216 NA 1-221 NA 1-222 NA 1-223 NA 1-224 NA 1-225 C 1-226 NA 1-227 NA 1-228 NA 1-229 B 1-230 C 1-231 NA 1-232 C 1-233 NA 1-234 C 1-235 NA 1-236 NA 1-237 NA 1-238 NA 1-239 NA 1-240 NA 1-241 NA 1-242 C 1-243 A 1-244 NA 1-245 NA 1-246 NA 1-247 NA 1-248 NA 1-249 NA 1-250 A 1-251 A

Example 253. Diet Induced Obesity Reversal Mouse Study

Male C57BL/6J mice aged 3 months were assigned to either normal chow diet (Chow, n=5) or western diet (WD, n=10) for 28 days, After 28 days half of the WD group were switched to WD containing compound 1412 at a concentration resulting in consumption of ˜60 mg/kg/day 1-112 (1-112 60 mpk). Body mass (A), fat mass (measured by EchoMRI (B)), and food intake (C, for the final 14 days) were recorded as indicated. Mice receiving WD containing 1-112 lost body weight and fat mass without a significant change in food intake.

Example 254. ROS Production Assay

Certain compounds of the disclosure also decrease ROS production, which can be measured in this assay. L6 myoblasts are seeded into black-walled clear-bottom 96-well microplates in L6 growth media and grown to confluence. Cells are then washed twice with PBS and co-incubated with 7.5 μM CM-H₂DCFDA and 0.5 ng/μL of each hit compound or vehicle control (DMSO) in KRP buffer (136 mM NaCl, 4.7 mM KCl, 10 mM NaPO₄, 0.9 mM MgSO₄, 0.9 mM CaCl₂, pH 7.4) supplemented with 25 mM D-glucose at 37° C. in 5% CO₂/95% air for 1 hr. 100 nM H₂O₂ is used as a positive control for ROS production. Following incubation, cells are washed three times with PBS to remove excess probe. Cells are then covered with 100 μL/well PBS and fluorescence intensity is measured by a Tecan Infinite® M200 microplate reader (Tecan Group Ltd., Switzerland) using a top-read configuration and with the excitation and emission filters set at 495±9 nm and 530±20 nm, respectively. Fluorescence data are recorded on Magellan (version 6.4) software and exported to Microsoft Excel for subsequent analysis. After subtracting the background fluorescence (that emitted from a well which does not receive the CM-H₂DCFDA probe) from each well, ROS production is expressed in terms of percentage fluorescence of the vehicle control for each condition. Compounds which increase ROS levels by greater than 20% are eliminated. 

What is claimed is:
 1. A compound of Formula I

or a pharmaceutically acceptable salts thereof, wherein X¹ and X² are C or N, with at least one of X¹ and X² being N; Z is O or S; R¹ is hydrogen or C₁-C₈alkyl, C₂-C₈alkenyl, or C₂-C₈alkynyl; R² is C₁-C₈alkyl, C₂-C₈alkenyl, or C₂-C₈alkynyl; or R² is —C₀-C₄alkyl(C₃-C₇cycloalkyl), —C₀-C₄alkyl(bridged C₇-C₁₂cycloalkyl), —C₀-C₄alkyl(aryl), —C₀-C₄alkyl(mono- or bi-cyclic heteroaryl), or —C₀-C₄alkyl(4- to 7-membered heterocycloalkyl), each of which is optionally substituted with one or more substituents independently chosen from R¹¹ and 0 or 1 substituents R¹²; or R¹ and R² are joined to form a 3-7 membered cyclic ring in which one carbon is optionally replaced by N, S, or O; R³ is H or C₁-C₈alkyl, C₂-C₈alkenyl, or C₂-C₈alkynyl, or R³ is —C₀-C₄alkyl(C₃-C₇cycloalkyl) or —C₀-C₄alkyl(aryl), which is optionally substituted with one or more independently chosen R¹¹ substituents; wherein in each C₀-C₄alkyl, C₁-C₈alkyl, C₂-C₈alkenyl, or C₂-C₈alkynyl in the definitions of R¹, R², and R³ one or more carbon atoms is optionally replaced by O, NR¹⁰, —C(O)—, —C(O)O—, —OC(O), —S(O)n-, —C(O)NR¹⁰—, or —NR¹⁰C(O)— where n is 0, 1, or 2, and in which the C₀-C₄alkyl, C₁-C₈ alkyl, C₂-C₈alkenyl, or C₂-C₈alkynyl is optionally substituted with one or more substituents R¹³; R¹⁰ is independently chosen at each occurrence from hydrogen, C₁-C₆alkyl, and —C₀-C₂alkyl(C₃-C₇cycloalkyl); R¹¹ is independently selected at each occurrence from halogen, hydroxyl, amino, nitro, cyano, —CHO, —COOH, oxo, halosulfanyl, and C₁-C₈alkyl, C₂-C₈alkenyl, and C₂-C₈alkynyl, wherein in each C₁-C₈alkyl, C₂-C₈alkenyl, and C₂-C₈alkynyl, in the definition of R¹¹ one or more carbon atoms is optionally replaced by O, NR¹⁰, —C(O)—, —C(O)O—, —OC(O), —S(O)n-, —S(O)nNR¹⁰, —NR¹⁰S(O)n-, —NR¹⁰C(O)NR¹⁰, —C(O)NR¹⁰—, or —NR¹⁰C(O)— where n is 0, 1, or 2, and in which each C₀-C₄alkyl, C₁-C₈alkyl, C₂-C₈alkenyl, or C₂-C₈alkynyl is optionally substituted with one or more substituents R¹³; R¹² is selected from —C₀-C₄alkyl(C₃-C₇cycloalkyl), —O—C₀-C₄alkyl(C₃-C₇cycloalkyl), —C₀-C₄alkyl(aryl), —O—C₀-C₄alkyl(aryl), —C₀-C₄alkyl(5- to 6-membered heteroaryl), —O—C₀-C₄alkyl(5- to 6-membered heteroaryl), —C₀-C₄alkyl(3- to 6-membered heterocycloalkyl), and —O—C₀-C₄alkyl(3- to 6-membered heterocycloalkyl), each of which is optionally substituted with one or more substituents independently chosen from halogen, hydroxyl, amino, nitro, cyano, —CHO, —COOH, oxo, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₆alkyl, C₁-C₆alkoxy, C₁-C₆alkylester, —C₀-C₄alkyl(mono- or di-C₁-C₆alkylamino), C₂-C₆alkanoyl, C₂-C₆alkenyl, and C₂-C₆alkynyl; and R¹³ is independently chosen at each occurrence from halogen, hydroxyl, amino, nitro, cyano, —CHO, —COOH, oxo, C₃-C₇cycloalkyl, and phenyl; with the proviso that when: (i) X¹ and X² are both N, Z is O, R¹ is methyl, and R³ is hydrogen, R² is not unsubstituted phenyl; and When X¹ and X² are both N, Z is O, and R¹ is hydrogen, (i) R² is not naphthyl, 3,4-di-chloro-phenyl, 4-methyl-phenyl, 3,4-dimethyl-phenyl, or 3-Cl,4-methyl-phenyl when R³ is hydrogen; (ii) R² is not 4-nitro-phenyl, when R³ is methyl; (iii) R² is not 3,4-di-chloro-phenyl, when R³ is naphthyl; and (iv) R² is not 3,4-di-chloro-phenyl, when R³ is 3,4-di-chloro-phenyl.
 2. A compound or salt thereof of claim 1, wherein Z is O and X¹ and X² are both nitrogen.
 3. A compound or salt thereof of claim 1, wherein Z is O and one of X¹ and X² is nitrogen and the other is carbon.
 4. A compound or salt thereof of any one of claims 1 to 3, wherein R¹ is hydrogen or unsubstituted C₁-C₆alkyl.
 5. A compound or salt thereof of claim 4, wherein R¹ is hydrogen.
 6. A compound or salt thereof of any one of claims 1 to 5, wherein R² is C₁-C₈alkyl, C₂-C₈alkenyl, or C₂-C₈alkynyl; in each C₀-C₄alkyl, C₁-C₈alkyl, C₂-C₈alkenyl, or C₂-C₈alkynyl one or more carbon atoms is optionally replaced by O, NR¹⁰, —C(O)—, —C(O)O—, —OC(O), —S(O)n-, —C(O)NR¹⁰—, or —NR¹⁰C(O)— where n is 0, 1, or 2, and in which the C₀-C₄alkyl, C₁-C₈ alkyl, C₂-C₈alkenyl, or C₂-C₈alkynyl is optionally substituted with one or more substituents R¹³.
 7. A compound or salt thereof of any one of claims 1 to 5, wherein R² is C₁-C₈alkyl, optionally substituted with one or more substituents independently chosen from halogen, hydroxyl, amino, nitro, cyano, and oxo.
 8. A compound or salt thereof of any one of claims 1 to 5, wherein R² is —C₀-C₄alkyl(C₃-C₇cycloalkyl), —C₀-C₄alkyl(bridged C₇-C₁₂cycloalkyl), —C₀-C₄alkyl(aryl), —C₀-C₄alkyl(mono- or bi-cyclic heteroaryl), or —C₀-C₄alkyl(4- to 7-membered heterocycloalkyl), each of which is optionally substituted with one or more substituents independently chosen from R¹¹ and 0 or 1 substituents R¹²; in each C₀-C₄alkyl, C₁-C₈alkyl, C₂-C₈alkenyl, or C₂-C₈alkynyl one or more carbon atoms is optionally replaced by O, NR¹⁰, —C(O)—, —C(O)O—, —OC(O), —S(O)n-, —C(O)NR¹⁰—, or —NR¹⁰C(O)— where n is 0, 1, or 2, and in which the C₀-C₄alkyl, C₁-C₈ alkyl, C₂-C₈alkenyl, or C₂-C₈alkynyl is optionally substituted with one or more substituents R¹³.
 9. A compound or salt thereof of claim 8, wherein R² is —C₀-C₄alkyl(bridged C₇-C₁₂cycloalkyl) or —C₀-C₄alkyl(aryl), each of which is optionally substituted with one or more substituents independently chosen from R¹¹ and 0 or 1 substituents R¹²; in C₀-C₄alkyl one or more carbon atoms is optionally replaced by O, NR¹⁰, —C(O)—, —C(O)O—, —OC(O), —S(O)n-, —C(O)NR¹⁰—, or —NR¹⁰C(O)— where n is 0, 1, or 2, and in which the C₀-C₄alkyl is optionally substituted by R¹³.
 10. A compound or salt thereof of claim 9, wherein R² is C₀-C₂alkyl(bridged C₇-C₁₂cycloalkyl), which is optionally substituted with one or more substituents independently chosen from R¹¹.
 11. A compound or salt thereof of claim 9, wherein R² is adamantan-1-yl or —CH₂(adamantan-1-yl), each of which is unsubstituted or substituted with halogen, hydroxyl, amino, nitro, cyano, C₁-C₄alkyl, C₁-C₄alkoxy, —C₀-C₂alkyl(mono- or di-C₁-C₄alkylamino), C₁-C₂haloalkyl, and C₁-C₂haloalkoxy.
 12. A compound or salt thereof of claim 9, wherein R² is —C₀-C₄alkyl(phenyl), naphthyl, benzo[d][1,3]dioxolyl, or fluorenyl, each of which is optionally substituted with one or more substituents independently chosen from R¹¹ and 0 or 1 substituents R¹²; in C₀-C₄alkyl one or more carbon atoms is optionally replaced by O, NR¹⁰, —C(O)—, —C(O)O—, —OC(O), —S(O)n-, —C(O)NR¹⁰—, —S(O)nNR¹⁰, —NR¹⁰S(O)n-, —NR¹⁰C(O)NR¹⁰, or —NR¹⁰C(O)— where n is 0, 1, or 2, and in which the C₀-C₄alkyl is optionally substituted by R¹³.
 13. A compound or salt thereof of claim 9, wherein R² is phenyl, which is optionally substituted by one or more substituents independently chosen from R¹¹.
 14. A compound or salt thereof of claim 9, wherein R² is phenyl, which is optionally substituted by one or more substituents independently chosen from halogen, hydroxyl, amino, nitro, cyano, oxo, halosulfanyl, and C₁-C₈alkyl, C₂-C₈alkenyl, and C₂-C₈alkynyl, wherein in each C₁-C₈alkyl, C₂-C₈alkenyl, and C₂-C₈alkynyl, in the definition of R¹¹ one or more carbon atoms is optionally replaced by O, NR¹⁰, —C(O)O—, —OC(O), or —S(O)n-, where n is 0, 1, or 2, and in which each C₁-C₈alkyl, C₂-C₈alkenyl, or C₂-C₈ alkynyl is optionally substituted with one or more substituents R¹³.
 15. A compound or salt thereof of claim 9 wherein: R² is —C₀-C₄alkyl(phenyl), which is optionally substituted with one or more substituents independently chosen from R¹¹ and 0 or 1 substituents R¹²; in C₀-C₄alkyl one or more carbon atoms is optionally replaced by O, NR¹⁰, —C(O)—, —C(O)O—, —OC(O), —S(O)n-, —C(O)NR¹⁰—, or —NR¹⁰C(O)— where n is 0, 1, or 2, and in which the C₀-C₄alkyl is optionally substituted by R¹³; R¹² is selected from —C₀-C₄alkyl(C₃-C₇cycloalkyl), —O—C₀-C₄alkyl(C₃-C₇cycloalkyl), —C₀-C₄alkyl(phenyl), —O—C₀-C₄alkyl(phenyl), —C₀-C₄alkyl(3- to 6-membered heteroaryl), —O—C₀-C₄alkyl(3- to 6-membered heteroaryl), each of which is optionally substituted with one or more substituents independently chosen from halogen, hydroxyl, amino, nitro, cyano, —CHO, —COOH, oxo, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₆alkyl, C₁-C₆alkoxy, C₁-C₆alkylester, —C₀-C₄alkyl(mono- or di-C₁-C₆alkylamino), C₂-C₆alkanoyl, C₂-C₆alkenyl, and C₂-C₆alkynyl.
 16. A compound or salt thereof of any one of claims 1 to 15, wherein R³ is hydrogen.
 17. A compound or salt thereof of any one of claims 1 to 15, wherein R³ is C₁-C₈alkyl, C₂-C₈alkenyl, or C₂-C₈alkynyl, in C₁-C₈alkyl, C₂-C₈alkenyl, or C₂-C₈alkynyl one or more carbon atoms is optionally replaced by O, NR¹⁰, C(O)O—, —OC(O), or —S(O)n-, where n is 0, 1, or 2, and in which the C₁-C₈ alkyl, C₂-C₈alkenyl, or C₂-C₈alkynyl is optionally substituted with one or more substituents R¹³.
 18. A compound or salt thereof of claim 17, wherein R³ is C₁-C₆alkyl optionally substituted with hydroxyl.
 19. A compound of salt thereof of any one of claims 1 to 15, wherein R³ is —C₀-C₄alkyl(C₃-C₇cycloalkyl) or —C₀-C₄alkyl(aryl), which is optionally substituted with one or more independently chosen R¹¹ substituents.
 20. A compound or salt thereof of claim 1, wherein X¹ and X² are C or N, with at least one of X¹ and X² being N; Z is O; R¹ is hydrogen or C₁-C₂alkyl; R² is C₁-C₈alkyl, C₂-C₈alkenyl, or C₂-C₈alkynyl; or R² is —C₀-C₄alkyl(C₃-C₇cycloalkyl), —C₀-C₄alkyl(bridged C₇-C₁₂cycloalkyl), —C₀-C₄alkyl(aryl), —C₀-C₄alkyl(mono- or bi-cyclic heteroaryl), or —C₀-C₄alkyl(4- to 7-membered heterocycloalkyl), each of which is optionally substituted with one or more substituents independently chosen from R¹¹ and 0 or 1 substituents R¹²; or R³ is H or C₁-C₆alkyl optionally substituted with hydroxyl; wherein in each C₀-C₄alkyl, C₁-C₈alkyl, C₂-C₈alkenyl, or C₂-C₈alkynyl in the definitions of R² one or more carbon atoms is optionally replaced by O, NR¹⁰, —C(O)O—, —OC(O), or —S(O)n-, where n is 0, 1, or 2, and in which the C₀-C₄alkyl, C₁-C₈ alkyl, C₂-C₈alkenyl, or C₂-C₈alkynyl is optionally substituted with one or more substituents R¹³; R¹⁰ is independently chosen at each occurrence from hydrogen, C₁-C₆alkyl, and —C₀-C₂alkyl(C₃-C₇cycloalkyl); R¹¹ is independently selected at each occurrence from halogen, hydroxyl, amino, nitro, cyano, —CHO, —COOH, oxo, halosulfanyl, and C₁-C₈alkyl, C₂-C₈alkenyl, and C₂-C₈alkynyl, wherein in each C₁-C₈alkyl, C₂-C₈alkenyl, and C₂-C₈alkynyl, in the definition of R¹¹ one or more carbon atoms is optionally replaced by O, NR¹⁰, —C(O)O—, —OC(O), or —S(O)n-, where n is 0, 1, or 2, and in which each C₁-C₈alkyl, C₂-C₈alkenyl, or C₂-C₈alkynyl is optionally substituted with one or more substituents R¹³; R¹² is selected from —C₀-C₄alkyl(C₃-C₇cycloalkyl), —O—C₀-C₄alkyl(C₃-C₇cycloalkyl), —C₀-C₄alkyl(aryl), —O—C₀-C₄alkyl(aryl), —C₀-C₄alkyl(5- to 6-membered heteroaryl), —O—C₀-C₄alkyl(5- to 6-membered heteroaryl), —C₀-C₄alkyl(3- to 6-membered heterocycloalkyl), and —O—C₀-C₄alkyl(3- to 6-membered heterocycloalkyl), each of which is optionally substituted with one or more substituents independently chosen from halogen, hydroxyl, amino, nitro, cyano, —CHO, —COOH, oxo, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₆alkyl, C₁-C₆alkoxy, C₁-C₆alkylester, —C₀-C₄alkyl(mono- or di-C₁-C₆alkylamino), C₂-C₆alkanoyl, C₂-C₆alkenyl, and C₂-C₆alkynyl; and R¹³ is independently chosen at each occurrence from halogen, hydroxyl, amino, nitro, cyano, —CHO, —COOH, oxo, C₃-C₇cycloalkyl, and phenyl.
 21. A compound or salt thereof of claim 20 in which X¹ and X² are both N.
 22. A compound or salt thereof of claim 1, wherein the compound is:


23. A pharmaceutical composition comprising a compound or salt thereof of any one of claims 1 to 22, together with a pharmaceutically acceptable carrier.
 24. A method of treating or decreasing the risk of developing a condition responsive to mitochondrial uncoupling, comprising administering a therapeutically effective amount of a compound or salt of any one of claims 1 to 22 to a patient in need of such treatment.
 25. The method of claim 24, wherein the condition responsive to mitochondrial uncoupling is obesity, type II diabetes, fatty liver disease, insulin resistance, multiple sclerosis, cancer, Huntington's disease, Alzheimer's dementia, Parkinson's disease, ischemia reperfusion injury, heart failure, non alcoholic fatty liver disease (NALFD), or non-alcoholic steatohepatitis (NASH)
 26. A method of regulating glucose homeostasis or insulin action in a patient comprising administering a therapeutically effective amount of a compound or salt of any one of claim 1 to 22 to the patient.
 27. A method of treating hyperlipidemia, glycemia, glucose tolerance, insulin sensitivity, adiposity, insulin resistance, obesity, or diabetes in a patient comprising administering a therapeutically effective amount of a compound of any one of claims 1 to 22 to the patient.
 28. A method for decreasing the risk of cancer in a patient at risk for cancer, comprising administering a therapeutically effective amount of a compound of any one of claims 1 to 22 to the patient.
 29. The method of claim 24, wherein the condition responsive to mitochondrial uncoupling is cancer and the cancer is a cancer having cancerous cells with impaired p53 expression or activity, a cancer with cancerous cells having a Ras mutation, a cancer with cancerous cells having a beta-catenin mutation, an adrenocortical carcinoma, melanoma, primary colon cancer, or a cancer with metastasis to the liver. 